Quinolone compound

ABSTRACT

The present invention provides a compound represented by the formula (T) 
     
       
         
         
             
             
         
       
     
     wherein X is a hydrogen atom or a fluorine atom; R is a hydrogen atom or alkyl; R 1  is (1) cyclopropyl optionally substituted by 1 to 3 halogen atoms or (2) phenyl optionally substituted by 1 to 3 halogen atoms; R 2  is alkyl, alkoxy, haloalkoxy, a halogen atom, cyano, etc.; and R 3  is 7-oxo-7,8-dihydro-1,8-naphthyridinyl, 3-pyridyl, etc., or a salt thereof. The compound of the present invention has excellent antimicrobial activity against  Clostridium difficile  and is useful for the prevention or treatment of intestinal infection such as  Clostridium difficile -associated diarrhea.

TECHNICAL FIELD

The present invention relates to quinolone compounds and pharmaceutical use thereof.

BACKGROUND ART

Clostridium difficile infection is associated with consumption of antibiotics which disrupt the normal microbial flora of the gut, allowing Clostridium difficile to establish itself and produce disease. Currently, only vancomycin or metronidazole is recommended for treatment and many patients suffer from relapse on infection (Expert Opin. Ther. Patents (2010) 20(10), pp. 1389-1399).

EP2177214 A1 describes use of ozenoxacin for Clostridium difficile.

Some quinolone compounds useful as antibacterial agents are disclosed in JP1-319463 A, WO99/51588, WO99/03465, JP3-66301 B and WO99/07682.

SUMMARY OF INVENTION

The object of the present invention is to provide a novel quinolone compound which has excellent antimicrobial activity, particularly excellent antimicrobial activity against Clostridium difficile. Another object of the present invention is to provide a pharmaceutical composition containing said quinolone compound, which is useful for the prevention or treatment of various infectious diseases including antibiotics-associated diarrhea (AAD) such as Clostridium difficile-associated diarrhea (CDAD). A further object of the present invention is to provide a method for preventing or treating a bacterial infection including AAD such as CDAD, which comprises administering said quinolone compound to a human or an animal.

The present invention provides a quinolone compound, a pharmaceutical composition comprising said compound, use of said compound, and a method for preventing or treating a bacterial infection, as described in Items 1 to 27 below.

Item 1. A compound represented by the formula (I)

wherein X is a hydrogen atom or a fluorine atom; R is a hydrogen atom or alkyl; R¹ is (1) cyclopropyl optionally substituted by 1 to 3 halogen atoms or (2) phenyl optionally substituted by 1 to 3 halogen atoms; R² is a hydrogen atom; alkyl optionally substituted by 1 or 2 substituents selected from the group consisting of a halogen atom and hydroxyl; alkoxy; haloalkoxy; a halogen atom; cyano; cyclopropyl; nitro; amino; formyl; alkenyl or alkynyl; or R¹ and R² are bonded to form a 5- or 6-membered ring optionally substituted by alkyl;

R³ is

-   (1) a fused heterocyclic group of the formula

wherein

represents a single bond or a double bond, X¹ is C(R⁵) or N, R⁴ is a hydrogen atom or alkyl, and R⁵ is (a) a hydrogen atom,

-   -   (b) a halogen atom,     -   (c) cyano,     -   (d) nitro,     -   (e) hydroxy,     -   (f) alkyl optionally substituted by 1 to 3 halogen atoms,     -   (g) alkenyl or alkynyl,     -   (h) aryl, or     -   (i) alkoxy optionally substituted by 1 to 3 halogen atoms,         when X¹ is C(R⁵), R⁴ and R⁵ are optionally bonded to form a 5-         or 6-membered ring optionally substituted by oxo,         said fused heterocyclic group is optionally substituted by 1 or         2 substituents selected from the group consisting of a halogen         atom, cyano, nitro, hydroxy and alkyl,

-   (2) a group of the formula

wherein X² is C(R⁸) or N, and R⁶, R⁷ and R⁸ are each independently,

-   -   (a) a hydrogen atom,     -   (b) a halogen atom,     -   (c) cyano,     -   (d) nitro,     -   (e) amino,     -   (f) alkyl optionally substituted by 1 to 3 substituents selected         from the group consisting of a halogen atom, alkoxy and amino,     -   (g) alkenyl,     -   (h) alkynyl,     -   (i) aryl,     -   (j) formyl or CH═N—OH,     -   (k) carboxy,     -   (l) carbamoyl,     -   (n) a 5- to 10-membered aromatic heterocyclic group optionally         substituted by alkyl, or     -   (n) alkenyloxy,

-   (3) a group of the formula

wherein X³ and X⁴ are N, or X³ is N and X⁴ is CR″, wherein R″ is hydrogen atom, amino, hydroxy, alkyl optionally substituted by 1 to 3 substituents selected from the group consisting of alkoxy and dimethylamino or mercapto, or X³ is CH and X⁴ is N, R′ is a hydrogen atom or alkyl optionally substituted by 1 to 3 substituents selected from the group consisting of substituted hydroxyl and amino, and R⁶ is as defined above,

-   (4) a group of the formula

wherein

represents a single bond or a double bond and R⁶ is as defined above,

-   (5) 3-pyridyl optionally substituted by 1 or 2 substituents selected     from the group consisting of     -   (a) a halogen atom,     -   (b) cyano,     -   (c) nitro,     -   (d) hydroxy,     -   (e) amino,     -   (f) alkyl optionally substituted by 1 to 3 substituents selected         from the group consisting of a halogen atom, alkylamino,         dialkylamino and hydroxy,     -   (g) alkenyl, alkynyl     -   (h) aryl,     -   (i) cycloalkyl,     -   (j) alkoxy,     -   (k) alkylamino,     -   (l) dialkylamino,     -   (m) phenylamino optionally substituted by 1 to 3 halogen atoms,     -   (n) a cyclic amino group optionally substituted by         alkoxycarbonyl,     -   (o) formyl,     -   (p) carbamoyl optionally substituted by alkyl optionally         substituted by hydroxy, and     -   (q) a 5- to 10-membered aromatic heterocyclic group optionally         substituted by alkyl, -   (6) 4-pyridyl optionally substituted by a halogen atom, -   (7) 5-pyrimidinyl optionally substituted by 1 or 2 substituents     selected from the group consisting of amino, alkylamino,     dialkylamino and carboxy, -   (8) 2-indolyl, 3-indolyl, 5-indolyl, 6-indolyl, benzofuranyl,     benzothiophenyl, benzoxazolyl or benzothiazolyl, each optionally     substituted by 1 or 2 substituents selected from the group     consisting of     -   (a) a halogen atom,     -   (b) cyano,     -   (c) nitro,     -   (d) hydroxy,     -   (e) alkyl optionally substituted by 1 to 3 substituents selected         from the group consisting of amino, alkoxycarbonylamino,         alkylamino and dialkylamino,     -   (f) alkoxy,     -   (g) formyl,     -   (h) carboxy, and     -   (j) amino optionally substituted by 1 or 2 substituents selected         from the group consisting of         -   (i) alkoxycarbonyl,         -   (ii) alkylcarbonyl optionally substituted by a substituent             selected from the group consisting of             -   (A) cycloalkyloxy optionally substituted by 1 to 3                 alkyl,             -   (B) alkylamino,             -   (C) dialkylamino,             -   (D) a cyclic amino group optionally substituted by                 alkoxycarbonyl, and             -   (E) a halogen atom,         -   (iii) phenylcarbonyl optionally substituted by 1 to 3             substituents selected from the group consisting of alkyl and             alkoxy,         -   (iv) cycloalkylcarbonyl,         -   (v) a 5- to 10-membered aromatic heterocyclylcarbonyl group             optionally substituted by alkyl optionally substituted by 1             to 3 halogen atoms,         -   (vi) benzylcarbonyl optionally substituted by 1 to 3             substituents selected from the group consisting of a halogen             atom and alkoxy,         -   (vii) arylsulfonyl optionally substituted by alkoxy,         -   (viii) cycloalkylalkylsulfonyl optionally substituted by 1             to 3 substituents selected from the group consisting of             alkyl and oxo,         -   (ix) a 5- to 10-membered aromatic heterocyclylsulfonyl group             optionally substituted by 1 to 3 alkyl, and         -   (x) —C(—N—CN)—SR⁹ wherein R⁹ is alkyl, -   (9) a group of the formula

wherein one of Y¹, Y², Y³ and Y⁴ is N or N⁺(—O⁻), and the remaining three are each C(R²⁵), C(R²⁶) and C(R²⁷)

W is O, S, NH or N(R³)

R²³ is a hydrogen atom or alkyl, and R²⁴, R²⁵, R²⁶ and R²⁷ are each independently,

-   -   (a) a hydrogen atom,     -   (b) cyano, or     -   (c) nitro,

-   (10) a group of the formula

wherein R²⁸ is a hydrogen atom or hydroxy, and R²⁹ is a hydrogen atom or alkyl,

-   (11) a group of the formula

wherein X⁵ is C(R¹¹) or N, X⁶ is CH₂, C(═O), O, S, SO₂ or N(R¹²), X⁷ is CH(R¹³), C(═O) or N(R¹⁴), X⁸ is CH(R¹⁵) or C(═O), R¹⁰, R¹² and R¹⁴ are each independently,

-   -   (a) a hydrogen atom or     -   (b) alkyl, and         R¹¹, R¹³ and R¹⁵ are each independently,     -   (a) a hydrogen atom,     -   (b) a halogen atom,     -   (c) cyano,     -   (d) nitro,     -   (e) amino,     -   (f) alkylamino,     -   (g) dialkylamino,     -   (h) alkyl optionally substituted by hydroxy, or     -   (i) alkenyl,         when X⁵ is C(R¹¹), R¹⁰ and R¹¹ are optionally bonded to form a         5- or 6-membered ring optionally substituted by alkyl or oxo,         and when X⁶ is N(R¹²) and X⁷ is CH(R¹³), R¹² and R¹³ are         optionally bonded to form a 5- or 6-membered ring,

-   (12) a group of the formula

wherein R¹⁶ is

-   -   (a) a hydrogen atom,     -   (b) alkyl optionally substituted by 1 to 3 substituents selected         from the group consisting of cyano, alkylamino and dialkylamino,     -   (c) alkenyl optionally substituted by carboxy,     -   (d) formyl,     -   (e) carboxy,     -   (f) carbamoyl,     -   (g) —C(R¹⁷)═N—OH wherein R¹⁷ is a hydrogen atom, cyano or         hydroxy,     -   (h) a 5- to 10-membered aromatic heterocyclic group optionally         substituted by alkyl, alkoxycarbonyl, carboxy or phenyl, or     -   (i) cyano,         (13) a group of the formula

wherein R¹⁸ is a hydrogen atom or alkyl optionally substituted by 1 to 3 substituents selected from the group consisting of a halogen atom and phenyl, n is 0 or 1, R¹⁹, R²⁰ and R³³ are each independently,

-   -   (a) a hydrogen atom,     -   (b) a halogen atom,     -   (c) cyano,     -   (d) alkyl optionally substituted by 1 to 3 substituents selected         from the group consisting of         -   (i) a halogen atom,         -   (ii) cyano,         -   (iii) hydroxy,         -   (iv) amino,         -   (v) alkylamino,         -   (vi) dialkylamino, and         -   (vii) a cyclic amino group optionally substituted by alkyl,     -   (e) alkoxy,     -   (f) amino optionally substituted by 1 or 2 substituents selected         from the group consisting of         -   (i) alkylcarbonyl optionally substituted by a cyclic amino             group,         -   (ii) alkylsulfonyl,         -   (iii) carbamoyl,         -   (iv) alkyl, cycloalkyl or cycloalkylalkyl, and         -   (v) 5- to 10-membered saturated heterocyclic group,     -   (g) carboxy,     -   (h) alkoxycarbonyl,     -   (i) carbamoyl optionally substituted by alkyl optionally         substituted by amino, alkylamino, dialkylamino or         alkoxycarbonylamino,     -   (j) formyl,     -   (k) a 5- to 10-membered aromatic heterocyclic group optionally         substituted by alkyl,     -   (l) —CH═N—OR²¹ wherein R²¹ is a hydrogen atom or alkyl         optionally substituted by alkylamino or dialkylamino,     -   (m) nitro,     -   (n) a 5- to 10-membered saturated heterocyclic group optionally         substituted by amino,     -   (o) phenyl, or     -   (p) —NHC(SMe)═CHCN,

-   (14) a group of the formula

wherein R³⁰ is (a) a hydrogen atom,

-   -   (b) a halogen atom,     -   (c) cyano,     -   (d) alkyl optionally substituted by 1 to 3 substituents selected         from the group consisting of a halogen atom and hydroxy,     -   (e) alkenyl,     -   (f) alkynyl,     -   (g) alkoxy,     -   (h) formyl,     -   (l) —CH═N—OH, or     -   (j) carbamoyl,

-   (15) naphthyl or isochromenyl,

-   (16) quinolyl or isoquinolyl, or their oxide derivatives,

-   (17) a group of the formula

-   (18) a group of the formula

wherein

U is O or S, and

R³¹ is (a) a hydrogen atom,

-   -   (b) a halogen atom,     -   (c) alkyl optionally substituted by 1 to 3 halogen atoms,     -   (d) carboxy,     -   (e) nitro,     -   (f) cyano, or     -   (g) amino,

-   (19) a group of the formula

wherein R³² is (a) a halogen atom,

-   -   (b) phenyl, or     -   (c) a group of the formula

-   (20) a group of the formula

wherein R³⁴ and R³⁵ are each independently,

-   -   (a) a hydrogen atom, or     -   (b) aminoalkyl,         or         R³⁴ and R³⁵ are bonded to form a 6-membered ring optionally         substituted by amino or oxo,

-   (21) a group of the formula

wherein R³⁶ is

-   -   (a) a hydrogen atom,     -   (b) a halogen atom,     -   (c) nitro, or     -   (d) thienyl, or         (22) a group of the formula

or a salt thereof.

Item 1A. The compound of item 1, wherein

X is a hydrogen atom or a fluorine atom; R is a hydrogen atom or alkyl; R¹ is (1) cyclopropyl optionally substituted by 1 to 3 halogen atoms or (2) phenyl optionally substituted by 1 to 3 halogen atoms; R² is alkyl, alkoxy, haloalkoxy, a chlorine atom or cyano; or R¹ and R² are bonded to form a 5- or 6-membered ring optionally substituted by alkyl; and

R³ is

-   (1) a fused heterocyclic group of the formula

wherein

represents a single bond or a double bond, X¹ is C(R⁵) or N, R⁴ is a hydrogen atom or alkyl, and R⁵ is (a) a hydrogen atom,

-   -   (b) a halogen atom,     -   (c) cyano,     -   (d) nitro,     -   (e) hydroxy,     -   (f) alkyl optionally substituted by 1 to 3 halogen atoms,     -   (g) alkenyl or alkynyl,     -   (h) aryl, or     -   (i) alkoxy optionally substituted by 1 to 3 halogen atoms,         when X is C(R⁵), R⁴ and R⁵ are optionally bonded to form a 5- or         6-membered ring optionally substituted by oxo,         said fused heterocyclic group is optionally substituted by 1 or         2 substituents selected from the group consisting of a halogen         atom, cyano, nitro, hydroxy and alkyl,         (2) a group of the formula

wherein X² is C(R⁸) or N, and R⁶, R⁷ and R⁸ are each independently,

-   -   (a) a hydrogen atom,     -   (b) a halogen atom,     -   (c) cyano,     -   (d) nitro,     -   (e) amino,     -   (f) alkyl optionally substituted by 1 to 3 substituents selected         from the group consisting of a halogen atom, alkoxy and amino,     -   (g) alkenyl,     -   (h) alkynyl,     -   (i) aryl,     -   (j) formyl or CH═N—OH,     -   (k) carboxy,     -   (l) carbamoyl, or     -   (m) a 5- to 10-membered aromatic heterocyclic group optionally         substituted by alkyl,         (3) a group of the formula

wherein X³ and X⁴ are N, or X³ is N and X⁴ is CR″, wherein R″ is a hydrogen atom, amino, hydroxy, alkyl or mercapto, or

X³ is CH and X is N,

R′ is a hydrogen atom or alkyl optionally substituted by 1 to 3 substituents selected from the group consisting of substituted hydroxy and amino, and R⁶ is as defined above,

-   (4) a group of the formula

wherein

represents a single bond or a double bond and R⁶ is as defined above,

-   (5) 3-pyridyl optionally substituted by 1 or 2 substituents selected     from the group consisting of     -   (a) a halogen atom,     -   (b) cyano,     -   (c) nitro,     -   (d) hydroxy,     -   (e) amino,     -   (f) alkyl optionally substituted by 1 to 3 substituents selected         from the group consisting of a halogen atom, alkylamino,         dialkylamino and hydroxy,     -   (g) alkenyl or alkynyl,     -   (h) aryl,     -   (i) cycloalkyl,     -   (j) alkoxy,     -   (k) alkylamino,     -   (l) dialkylamino,     -   (m) phenylamino optionally substituted by 1 to 3 halogen atoms,     -   (n) a cyclic amino group optionally substituted by         alkoxycarbonyl,     -   (o) formyl,     -   (p) carbamoyl optionally substituted by alkyl optionally         substituted by hydroxy, and     -   (q) a 5- to 10-membered aromatic heterocyclic group optionally         substituted by alkyl, -   (6) 4-pyridyl optionally substituted by a halogen atom, -   (7) 5-pyrimidinyl optionally substituted by 1 or 2 substituents     selected from the group consisting of amino, alkylamino,     dialkylamino and carboxy, -   (8) 2-indolyl, 3-indolyl, 5-indolyl, 6-indolyl, benzofuranyl,     benzothiophenyl, benzoxazolyl or benzothiazolyl, each optionally     substituted by 1 or 2 substituents selected from the group     consisting of     -   (a) a halogen atom,     -   (b) cyano,     -   (c) nitro,     -   (d) hydroxy,     -   (e) alkyl optionally substituted by 1 to 3 substituents selected         from the group consisting of amino, alkoxycarbonylamino,         alkylamino and dialkylamino,     -   (f) alkoxy,     -   (g) formyl,     -   (h) carboxy, and     -   (j) amino optionally substituted by 1 or 2 substituents selected         from the group consisting of         -   (i) alkoxycarbonyl,         -   (ii) alkylcarbonyl optionally substituted by a substituent             selected from the group consisting of             -   (A) cycloalkyloxy optionally substituted by 1 to 3                 alkyl,             -   (B) alkylamino,             -   (C) dialkylamino,             -   (D) a cyclic amino group optionally substituted by                 alkoxycarbonyl, and             -   (E) a halogen atom,         -   (iii) phenylcarbonyl optionally substituted by 1 to 3             substituents selected from the group consisting of alkyl and             alkoxy,         -   (iv) cycloalkylcarbonyl,         -   (v) a 5- to 10-membered aromatic heterocyclylcarbonyl group             optionally substituted by alkyl optionally substituted by to             3 halogen atoms,         -   (vi) benzylcarbonyl optionally substituted by 1 to 3             substituents selected from the group consisting of a halogen             atom and alkoxy,         -   (vii) arylsulfonyl optionally substituted by alkoxy,         -   (viii) cycloalkylalkylsulfonyl optionally substituted by 1             to 3 substituents selected from the group consisting of             alkyl and oxo,         -   (ix) a 5- to 10-membered aromatic heterocyclylsulfonyl group             optionally substituted by 1 to 3 alkyl, and         -   (x) —C(═N—CN)—SR⁹ wherein R⁹ is alkyl, -   (9) a group of the formula

wherein one of Y, Y², Y³ and Y⁴ is N or N⁺(—O⁻), and the remaining three are each C(R²⁵), C(R²⁶) and C(R²⁷),

W is O, S or N(R²³)

R²³ is a hydrogen atom or alkyl, and R²⁴, R²⁶ and R²⁷ are each independently,

-   -   (a) a hydrogen atom,     -   (b) cyano, or     -   (c) nitro,

-   (10) a group of the formula

wherein R²⁸ is a hydrogen atom or hydroxy, and R²⁹ is a hydrogen atom or alkyl,

-   (11) a group of the formula

wherein X⁵ is C(R¹¹) or N, X⁶ is CH₂, C(═O), O, S, SO₂ or N(R¹²), X⁷ is CH(R¹³), C(═O) or N(R¹⁴), X⁸ is CH(R¹⁵) or C(═O), R¹⁰, R¹² and R¹⁴ are each independently,

-   -   (a) a hydrogen atom or     -   (b) alkyl, and         R¹¹, R¹³ and R¹⁵ are each independently,     -   (a) a hydrogen atom,     -   (b) a halogen atom,     -   (c) cyano,     -   (d) nitro,     -   (e) amino,     -   (f) alkylamino,     -   (g) dialkylamino,     -   (h) alkyl optionally substituted by hydroxy, or     -   (i) alkenyl,         when X⁵ is C(R¹), R¹⁰ and R¹¹ are optionally bonded to form a 5-         or 6-membered ring optionally substituted by alkyl or oxo, and         when X⁶ is N(R¹²) and X⁷ is CH(R¹³), R¹² and R¹³ are optionally         bonded to form a 5- or 6-membered ring,

-   (12) a group of the formula

wherein R¹⁶ is

-   -   (a) a hydrogen atom,     -   (b) alkyl optionally substituted by 1 to 3 substituents selected         from the group consisting of cyano, alkylamino and dialkylamino,     -   (c) alkenyl optionally substituted by carboxy,     -   (d) formyl,     -   (e) carboxy,     -   (f) carbamoyl,     -   (g) —C(R¹⁷)—N—OH wherein R¹⁷ is a hydrogen atom, cyano or         hydroxy,     -   (h) a 5- to 10-membered aromatic heterocyclic group optionally         substituted by alkyl, alkoxycarbonyl, carboxy or phenyl, or     -   (i) cyano,

-   (13) a group of the formula

wherein R¹⁸ is a hydrogen atom or alkyl optionally substituted by 1 to 3 substituents selected from the group consisting of a halogen atom and phenyl, and R¹⁹ and R²⁰ are each independently,

-   -   (a) a hydrogen atom,     -   (b) a halogen atom,     -   (c) cyano,     -   (d) alkyl optionally substituted by 1 to 3 substituents selected         from the group consisting of         -   (i) a halogen atom,         -   (ii) cyano,         -   (iii) hydroxy,         -   (iv) amino,         -   (v) alkylamino,         -   (vi) dialkylamino, and         -   (vii) a cyclic amino group optionally substituted by alkyl,     -   (e) alkoxy,     -   (f) amino optionally substituted by 1 or 2 substituents selected         from the group consisting of         -   (i) alkylcarbonyl optionally substituted by a cyclic amino             group,         -   (ii) alkylsulfonyl,         -   (iii) carbamoyl, and         -   (iv) alkyl or cycloalkyl,     -   (g) carboxy,     -   (h) alkoxycarbonyl,     -   (i) carbamoyl optionally substituted by alkyl optionally         substituted by amino, alkylamino, dialkylamino or         alkoxycarbonylamino,     -   (j) formyl,     -   (k) a 5- to 10-membered aromatic heterocyclic group optionally         substituted by alkyl,     -   (l) —CH═N—OR²¹ wherein R²¹ is a hydrogen atom or alkyl         optionally substituted by alkylamino or dialkylamino, or     -   (m) nitro,

-   (14) a group of the formula

wherein R³⁰ is (a) a hydrogen atom,

-   -   (b) a halogen atom,     -   (c) cyano,     -   (d) alkyl optionally substituted by 1 to 3 substituents selected         from the group consisting of a halogen atom and hydroxy,     -   (e) alkenyl,     -   (f) alkynyl,     -   (g) alkoxy,     -   (h) formyl, or     -   (i) —CH═N—OH,

-   (15) naphthyl or isochromenyl, or

-   (16) quinolyl or isoquinolyl, or oxide derivative thereof, or a salt     thereof.

Item 2. The compound of item 1 or 1A, wherein X is a fluorine atom, or a salt thereof.

Item 3. The compound of item 1 or 1A, wherein R³ is a fused heterocyclic group of the formula

wherein

, X¹ and R⁴ are as defined in item 1, and said fused heterocyclic group is optionally substituted by 1 or 2 substituents selected from the group consisting of a halogen atom, cyano, nitro, hydroxy and alkyl, or a salt thereof.

Item 4. The compound of item 1 or 1A, wherein R³ is a group of the formula

wherein X², R⁵ and R⁷ are as defined in item 1, or a salt thereof.

Item 5. The compound of item 1 or 1A, wherein R³ is a group of the formula

wherein X³, X⁴, R⁶ and R′ are as defined in item 1, or a salt thereof.

Item 6. The compound of item 1 or 1A, wherein R³ is a group of the formula

wherein

and R⁶ are as defined in item 1, or a salt thereof.

Item 7. The compound of item 1 or 1A, wherein R³ is a group of the formula

wherein R²² is

-   -   (a) a halogen atom,     -   (b) cyano,     -   (c) nitro,     -   (d) alkyl optionally substituted by 1 to 3 substituents selected         from the group consisting of a halogen atom, alkylamino,         dialkylamino and hydroxy,     -   (e) alkenyl or alkynyl,     -   (f) aryl,     -   (g) cycloalkyl,     -   (h) alkoxy,     -   (i) formyl, or     -   (j) carbamoyl optionally substituted by alkyl optionally         substituted by hydroxy,         or a salt thereof.

Item 8. The compound of item 1 or 1A, wherein R³ is 5-pyrimidinyl substituted by 1 or 2 substituents selected from the group consisting of amino, alkylamino, dialkylamino and carboxy, or a salt thereof.

Item 9. The compound of item 1 or 1A, wherein R³ is 2-indolyl optionally substituted by 1 or 2 substituents selected from the group consisting of

-   -   (a) a halogen atom,     -   (b) cyano,     -   (c) nitro,     -   (d) hydroxy,     -   (e) alkyl optionally substituted by 1 to 3 substituents selected         from the group consisting of amino, alkoxycarbonylamino,         alkylamino and dialkylamino,     -   (f) alkoxy,     -   (g) formyl,     -   (h) carboxy, and     -   (j) amino optionally substituted by 1 or 2 substituents selected         from the group consisting of         -   (i) alkoxycarbonyl,         -   (ii) alkylcarbonyl optionally substituted by a substituent             selected from the group consisting of             -   (A) cycloalkyloxy optionally substituted by 1 to 3                 alkyl,             -   (B) alkylamino,             -   (C) dialkylamino,             -   (D) a cyclic amino group optionally substituted by                 alkoxycarbonyl, and             -   (E) a halogen atom,         -   (iii) phenylcarbonyl optionally substituted by 1 to 3             substituents selected from the group consisting of alkyl and             alkoxy,         -   (iv) cycloalkylcarbonyl,         -   (v) a 5- to 10-membered aromatic heterocyclylcarbonyl group             optionally substituted by alkyl optionally substituted by 1             to 3 halogen atoms,         -   (vi) benzylcarbonyl optionally substituted by 1 to 3             substituents selected from the group consisting of a halogen             atom and alkoxy,         -   (vii) arylsulfonyl optionally substituted by alkoxy,         -   (viii) cycloalkylalkylsulfonyl optionally substituted by 1             to 3 substituents selected from the group consisting of             alkyl and oxo,         -   (ix) a 5- to 10-membered aromatic heterocyclylsulfonyl group             optionally substituted by 1 to 3 alkyl, and         -   (x) —C(═N—CN)—SR⁹ wherein R⁹ is alkyl, or a salt thereof.

Item 10. The compound of item 1 or 1A, wherein R³ is a group of the formula

wherein Y¹, Y², Y³, Y⁴, W and R²⁴ are as defined in item 1, or a salt thereof.

Item 11. The compound of item 1 or 1A, wherein R³ is a group of the formula

wherein R²⁸ and R²⁹ are as defined in item 1, or a salt thereof.

Item 12. The compound of item 1 or 1A, wherein R³ is a group of the formula

wherein X⁵, X⁶, X⁷, X⁸ and R¹⁰ are as defined in item 1, or a salt thereof.

Item 13. The compound of item 1 or 1A, wherein R³ is a group of the formula

wherein R^(16a) is

-   -   (a) alkyl optionally substituted by 1 to 3 substituents selected         from the group consisting of cyano, alkylamino and dialkylamino,     -   (b) alkenyl optionally substituted by carboxy,     -   (c) formyl,     -   (d) carboxy,     -   (e) carbamoyl,     -   (f) —C(R′)═N—OH wherein R¹⁷ is a hydrogen atom, cyano or         hydroxy,     -   (g) a 5- to 10-membered aromatic heterocyclic group optionally         substituted by alkyl, alkoxycarbonyl, carboxy or phenyl, or     -   (h) cyano,         or a salt thereof.

Item 14. The compound of item 1 or 1A, wherein R³ is a group of the formula

wherein R^(18a) is alkyl, and R^(19a) is (a) a halogen atom,

-   -   (b) cyano,     -   (c) alkyl optionally substituted by 1 to 3 substituents selected         from the group consisting of         -   (i) a halogen atom,         -   (ii) cyano,         -   (iii) hydroxy,         -   (iv) amino,         -   (v) alkylamino,         -   (vi) dialkylamino, and         -   (vii) a cyclic amino group optionally substituted by alkyl,     -   (d) alkoxy,     -   (e) amino optionally substituted by 1 or 2 substituents selected         from the group consisting of         -   (i) alkylcarbonyl optionally substituted by a cyclic amino             group,         -   (ii) alkylsulfonyl,         -   (iii) carbamoyl, and         -   (iv) alkyl or cycloalkyl,     -   (f) carboxy,     -   (g) alkoxycarbonyl,     -   (h) carbamoyl optionally substituted by alkyl optionally         substituted by amino, alkylamino, dialkylamino or         alkoxycarbonylamino,     -   (i) formyl,     -   (j) a 5- to 10-membered aromatic heterocyclic group optionally         substituted by alkyl,     -   (k) —CH═N—OR²¹ wherein R is a hydrogen atom or alkyl optionally         substituted by alkylamino or dialkylamino, or     -   (l) nitro,         or a salt thereof.

Item 15. The compound of item 1 or 1A, wherein R³ is a group of the formula

wherein R³⁰ is as defined in item 1, or a salt thereof.

Item 16. The compound of item 1 or 1A, wherein R³ is naphthyl or isochromenyl, or a salt thereof.

Item 17. The compound of item 1 or 1A, wherein R³ is quinolyl or isoquinolyl, or oxide derivative thereof, or a salt thereof.

Item 18. The compound of item 1 or 1A, wherein R is a hydrogen atom, or a salt thereof.

Item 19. The compound of item 1 or 1A, wherein R¹ is cyclopropyl, 2-fluorocyclopropyl or 2,4-difluorophenyl, or a salt thereof.

Item 20. The compound of item 1 or 1A, wherein R² is methyl, methoxy or a chlorine atom, or a salt thereof.

Item 21. A pharmaceutical composition comprising a compound of item 1 or 1A or a salt thereof and a pharmaceutically acceptable carrier.

Item 22. An antimicrobial agent comprising a compound of item 1 or 1A or a salt thereof.

Item 23. A compound of item 1 or 1A or a salt thereof for use as a medicament.

Item 24. A compound of item 1 or 1A or a salt thereof for use as an antimicrobial agent.

Item 25. A compound of item 1 or 1A or a salt thereof for use in the prevention or treatment of a bacterial infection.

Item 26. Use of a compound of item 1 or 1A or a salt thereof for the manufacture of a medicament for preventing or treating a bacterial infection.

Item 27. A method for preventing or treating a bacterial infection which comprises administering an effective amount of a compound of item 1 or 1A or a salt thereof to a human or an animal.

The compound of the formula (I) or a salt thereof (hereinafter sometimes to be abbreviated as compound (I)) has excellent antibacterial activity against various gram positive and gram negative bacteria, and is useful for the prevention or treatment of various infectious diseases induced by various bacteria in human, other animals and fish and is also useful as an external antimicrobial or disinfectant agent for medical instruments or the like.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 is a graph showing the results of the animals administered with compound 2-18 in Experimental Example 2.

FIG. 2 is a graph showing the results of the animals administered with vancomycin in Experimental Example 2.

DETAILED DESCRIPTION OF THE INVENTION

Specific examples of groups in the formula (I) are as follows.

Examples of “halogen atom” include fluorine atom, chlorine atom, bromine atom, and iodine atom.

Examples of “alkyl” and “alkyl” moiety in “alkylamino”, “dialkylamino”, “alkylcarbonyl”, “cycloalkylalkylsulfonyl”, “cycloalkylalkyl”, “aminoalkyl” and “alkylsulfonyl” include straight or branched C₁₋₆ alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 1-ethylpropyl, isopentyl, neopentyl, tert-pentyl, hexyl, 1,2,2-trimethylpropyl, 3,3-dimethylbutyl, 2-ethylbutyl, isohexyl, 3-methylpentyl, etc.

Examples of “alkenyl” include straight or branched C₂₋₆ alkenyl such as vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-2-propenyl, 2-pentenyl, 2-hexenyl, etc.

Examples of “alkynyl” include straight or branched C₂₋₆ alkynyl such as ethynyl, 2-propynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 2-pentynyl, 2-hexynyl, etc.

Examples of “alkoxy” and “alkoxy” moiety in “haloalkoxy”, “alkoxycarbonyl” and “alkoxycarbonylamino” include straight or branched C₁₋₆ alkoxy such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, tert-pentyloxy, hexyloxy, isohexyloxy, 3-methylpentyloxy, etc.

Examples of “haloalkoxy” include straight or branched C₁₋₆ alkoxy substituted by 1 to 3 halogen atoms. Examples thereof include fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, trichloromethoxy, bromomethoxy, dibromomethoxy, dichlorofluoromethoxy, 2,2,2-trifluoroethoxy, 2-chloroethoxy, 3,3,3-trifluoropropoxy, 2-chloropropoxy, 3-chloropropoxy, 3-bromopropoxy, 4,4,4-trifluorobutoxy, 2-chlorobutoxy, 4-chlorobutoxy, 4-bromobutoxy, 5,5,5-trifluoropentyloxy, 5-chloropentyloxy, 6,6,6-trifluorohexyloxy, 6-chlorohexyloxy, etc. Preferable examples thereof include difluoromethoxy.

Examples of “alkenyloxy” include straight or branched C₂₋₆ alkenyloxy such as vinyloxy, 1-propenyloxy, 2-propenyloxy, 1-butenyloxy, 2-butenyloxy, 3-butenyloxy, 1-methyl-2-propenyloxy, 2-pentenyloxy, 2-hexenyloxy, etc.

Examples of “aryl” and “aryl” moiety in “arylsulfonyl” include C₆₋₁₄ (preferably C₁₋₁₀) aryl such as phenyl, naphthyl (e.g., 1-naphthyl, 2-naphthyl), etc. Preferable examples thereof include phenyl.

Examples of “5- to 10-membered aromatic heterocyclic group” and “5- to 10-membered aromatic heterocyclyl” moiety in “5- to 10-membered aromatic heterocyclylcarbonyl group” and “5- to 10-membered aromatic heterocyclylsulfonyl group” include 5- to 10-membered (preferably 5- or 6-membered) aromatic heterocyclic group containing 1 to 4 (preferably 1 to 3, more preferably 1 or 2) heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom. Examples thereof include furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl (e.g., 1,2,3-triazolyl, 1,2,4-triazolyl), tetrazolyl, isoxazolyl, oxazolyl, furazanyl, isothiazolyl, thiazolyl, pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl), pyridazinyl, pyrimidinyl, pyrazinyl, benzofuranyl, isobenzofuranyl, benzo[b]thiophenyl, benzo[c]thiophenyl, indolyl, isoindolyl, indolizinyl, indazolyl, benzimidazolyl, benzotriazolyl, benzoxazolyl, 1,2-benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, purinyl, quinolyl, isoquinolyl, quinolizinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl, pteridinyl, etc. Preferable examples thereof include pyrrolyl, imidazolyl, oxazolyl, triazolyl (e.g., 1,2,3-triazolyl, 1,2,4-triazolyl), tetrazolyl, pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl), benzimidazolyl, etc.

Examples of “alkylamino” include C₁₋₆ alkylamino such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, sec-butylamino, tert-butylamino, pentylamino, isopentylamino, neopentylamino, tert-pentylamino, hexylamino, etc.

Examples of “dialkylamino” include di(C₁₋₆ alkyl) amino such as dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, diisobutylamino, di(sec-butyl)amino, di(tert-butyl)amino, dipentylamino, di(tert-pentyl)amino, dihexylamino, ethylmethylamino, etc.

Examples of “aminoalkyl” include amino-C₁₋₆ alkyl such as aminomethyl, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl, 6-aminohexyl, etc.

Examples of “cycloalkyl” and “cycloalkyl” moiety in “cycloalkyloxy”, “cycloalkylcarbonyl”, “cycloalkylalkyl” and “cycloalkylalkylsulfonyl” include C₃₋₈ cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornanyl (e.g., 2-norbornanyl), etc.

Examples of “cycloalkylalkyl” include C₃₋₈ cycloalkyl-C₁₋₆ alkyl such as cycopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclooctylmethyl, norbornanylmethyl (e.g., norbornan-2-ylmethyl), etc.

Examples of “cyclic amino group” includes a 4- to 7-membered (preferably 5- or 6-membered) cyclic amino group containing one nitrogen atom and optionally further containing one heteroatom selected from a nitrogen atom, an oxygen atom and a sulfur atom. Examples thereof include 1-azetidinyl, 1-pyrrolidinyl, 1-imidazolidinyl, 1-pyrazolidinyl, piperidino, 1-piperazinyl, morpholino, thiomorpholino, 1-azepanyl, 1,4-oxazepan-4-yl, etc. Preferable examples thereof include 1-pyrrolidinyl, piperidino, 1-piperazinyl, morpholino, thiomorpholino, etc.

Examples of “alkoxycarbonyl” include C₁₋₆ alkoxy-carbonyl wherein the alkoxy moiety is C₁₋₆ alkoxy. Examples thereof include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, so hexyloxycarbonyl, etc.

Examples of “alkoxycarbonylamino” include C₁₋₆ alkoxy-carbonylamino wherein the alkoxy moiety is C₁₋₆ alkoxy. Examples thereof include methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, isopropoxycarbonylamino, butoxycarbonylamino, isobutoxycarbonylamino, sec-butoxycarbonylamino, tert-butoxycarbonylamino, pentyloxycarbonylamino, hexyloxycarbonylamino, etc.

Examples of “alkylcarbonyl” include C₁₋₆ alkyl-carbonyl wherein the alkyl moiety is C₁₋₆ alkyl. Examples thereof include acetyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, butylcarbonyl, isobutylcarbonyl, sec-butylcarbonyl, tert-butylcarbonyl, pentylcarbonyl, hexylcarbonyl, etc.

Examples of “cycloalkyloxy” include C₃₋₈ cycloalkyloxy such as cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, cyclooctyloxy, etc.

Examples of “cycloalkylcarbonyl” include C₃₋₈ cycloalkyl-carbonyl such as cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, cycloheptylcarbonyl, cyclooctylcarbonyl, etc.

Examples of “5- to 10-membered aromatic heterocyclylcarbonyl group” include a 5- to 10-membered (preferably 5- or 6-membered) aromatic heterocyclylcarbonyl group wherein the heterocyclyl moiety contains 1 to 4 (preferably 1 to 3, more preferably 1 or 2) heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom. Examples of the heterocyclyl moiety are same as the examples of the 5- to 10-membered aromatic heterocyclic group mentioned above. Preferable examples of “5- to 10-membered aromatic heterocyclylcarbonyl group” include pyridylcarbonyl (e.g., 2-pyridylcarbonyl, 3-pyridylcarbonyl, 4-pyridylcarbonyl).

Examples of “arylsulfonyl” include C₆₋₁₄ (preferably C₆₋₁₀) arylsulfonyl such as phenylsulfonyl, naphthylsulfonyl (e.g., 1-naphthylsulfonyl, 2-naphthylsulfonyl), etc. Preferable examples thereof include phenylsulfonyl.

Examples of “cycloalkylalkylsulfonyl” include C₃₋₈ cycloalkyl-C₁₋₆ alkylsulfonyl such as cyclopropylmethylsulfonyl, cyclobutylmethylsulfonyl, cyclopentylmethylsulfonyl, cyclohexylmethylsulfonyl, cycloheptylmethylsulfonyl, cyclooctylmethylsulfonyl, norbornanylmethylsulfonyl (e.g., norbornan-2-ylmethylsulfonyl), etc.

Examples of “5- to 10-membered aromatic heterocyclylsulfonyl group” include a 5- to 10-membered (preferably 5- or 6-membered) aromatic heterocyclylsulfonyl group wherein the heterocyclyl moiety contains 1 to 4 (preferably 1 to 3, more preferably 1 or 2) heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom. Examples of the heterocyclyl moiety are same as the examples of the 5- to 10-membered aromatic heterocyclic group mentioned above. Preferable examples of “5- to 10-membered aromatic heterocyclylsulfonyl group” include imidazolylsulfonyl.

Examples of “alkylsulfonyl” include C₁₋₆ alkylsulfonyl wherein the alkyl moiety is C₁₋₆ alkyl. Examples thereof include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl, pentylsulfonyl, hexylsulfonyl, etc.

Examples of “cyclopropyl optionally substituted by 1 to 3 halogen atoms” include cyclopropyl optionally substituted by 1 fluorine atom such as cyclopropyl, 2-fluorocyclopropyl, etc.

Examples of “phenyl optionally substituted by 1 to 3 halogen atoms” include phenyl substituted by two fluorine atoms such as 2,4-difluorophenyl, etc.

Examples of “5- to 10-membered saturated heterocyclic group” include a 5- to 10-membered (preferably 5- or 6-membered) saturated heterocyclic group containing 1 to 4 (preferably 1 to 3, more preferably 1 or 2) heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom. Examples thereof include pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, etc.

Examples of “6-membered ring optionally substituted by amino or oxo” formed by R³⁴ and R³⁵ include a 6-membered ring optionally containing one nitrogen atom, and said ring is optionally substituted by amino or oxo. Examples thereof include cyclohexene and dihydropyridine, each optionally substituted by amino or oxo.

Examples of “5- or 6-membered ring optionally substituted by alkyl” formed by R¹ and R² include a 5- or 6-membered (preferably 6-membered) ring containing one nitrogen atom and optionally further containing one oxygen atom, and said ring is optionally substituted by alkyl. Preferably, R¹ and R² are optionally bonded to form —CH₂—CH(CH₃)— wherein the oxygen atom is bonded to the phenyl ring of the quinolone ring as shown below.

Examples of “5- or 6-membered ring optionally substituted by oxo” formed by R⁴ and R⁵ include a 5- or 6-membered (preferably 6-membered) ring containing one nitrogen atom and optionally further containing one oxygen atom, and said ring is optionally substituted by oxo. Preferably, R⁴ and R⁵ are optionally bonded to form —CH₂—O—(C═O)— wherein the carbonyl is bonded to the phenyl ring of the quinolone ring as shown below.

Examples of “5- or 6-membered ring optionally substituted by alkyl or oxo” formed by R¹⁰ and R¹¹ include a 5- or 6-membered (preferably 5-membered) ring containing 2 or 3 nitrogen atoms, and said ring is optionally substituted by alkyl or oxo. Preferably, R¹⁰ and R¹¹ are optionally bonded to form —(C═O)—NH—, —C(R³¹)═N— or —N═N— wherein R³¹ is a hydrogen atom or alkyl, and the nitrogen atom is bonded to the phenyl ring of the fused ring, as shown below.

Examples of “5- or 6-membered ring” formed by R¹² and R¹³ include a 5- or 6-membered (preferably 6-membered) ring containing one nitrogen atom. Preferably, R¹² and R¹³ are optionally bonded to form —(CH₂)₄— as shown below.

X is a hydrogen atom or a fluorine atom, preferably, a fluorine atom.

R is a hydrogen atom or alkyl, preferably, a hydrogen atom.

R¹ is (1) cyclopropyl optionally substituted by 1 to 3 halogen atoms or (2) phenyl optionally substituted by 1 to 3 halogen atoms, preferably, cyclopropyl, 2-fluorocyclopropyl or 2,4-difluorophenyl.

R² is a hydrogen atom; alkyl optionally substituted by 1 or 2 substituents selected from the group consisting of a halogen atom and hydroxyl; alkoxy; haloalkoxy; a halogen atom; cyano; cyclopropyl; nitro; amino; formyl; alkenyl or alkynyl, preferably, alkyl, alkoxy, haloalkoxy, a chlorine atom or cyano, more preferably, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ alkoxy substituted by 1 to 3 halogen atoms, a chlorine atom or cyano, still more preferably, methyl, methoxy or a chlorine atom.

Examples of a fused heterocyclic group of the formula (A) or (B) include a fused heterocyclic group of the formula

wherein X¹ and R⁴ are as defined above, and said fused heterocyclic group is optionally substituted by 1 or 2 substituents selected from the group consisting of a halogen atom, cyano, nitro, hydroxy and alkyl.

Preferable examples of a fused heterocyclic group of the formula (A) or (B) include a fused heterocyclic group of the formula

wherein R⁴ and R⁵ are as defined above, and said fused heterocyclic group is optionally substituted by 1 or 2 substituents selected from the group consisting of a halogen atom, cyano, nitro, hydroxy and alkyl.

Other preferable examples of a fused heterocyclic group of the formula (A) or (B) include a fused heterocyclic group of the

wherein X¹ and R⁴ are as defined above, and said fused heterocyclic group is optionally substituted by 1 or 2 substituents selected from the group consisting of a halogen atom, cyano, nitro, hydroxy and alkyl.

Examples of a group of the formula (C) include a group of the formula

wherein X², R⁶ and R⁷ are as defined above.

Preferable examples of a group of the formula (C) include a group of the formula

wherein R⁶, R⁷ and R⁸ are as defined above.

In the above formulas, R⁶, R⁷ and R⁸ are each independently,

-   -   (a) a hydrogen atom,     -   (b) a halogen atom,     -   (c) cyano,     -   (d) nitro,     -   (e) amino,     -   (f) alkyl optionally substituted by 1 to 3 substituents selected         from the group consisting of a halogen atom and amino,     -   (g) alkenyl,     -   (h) alkynyl,     -   (i) aryl,     -   (j) formyl,     -   (k) carboxy,     -   (l) carbamoyl, or     -   (m) a 5- to 10-membered aromatic heterocyclic group (e.g.,         pyridyl, triazolyl) optionally substituted by alkyl.

Examples of a group of the formula (D) or (E) include a group of the formula

wherein R⁶ is as defined above. R⁶ is preferably a hydrogen atom, a halogen atom, nitro or amino.

Preferably, R³ is 3-pyridyl optionally substituted by 1 or 2 substituents selected from the group consisting of

-   -   (a) a halogen atom,     -   (b) cyano,     -   (c) nitro,     -   (d) hydroxy,     -   (e) amino,     -   (f) alkyl optionally substituted by 1 to 3 substituents selected         from the group consisting of a halogen atom, alkylamino,         dialkylamino and hydroxy,     -   (g) alkenyl,     -   (h) aryl,     -   (i) cycloalkyl,     -   (j) alkoxy,     -   (k) alkylamino,     -   (l) dialkylamino,     -   (m) phenylamino optionally substituted by 1 to 3 halogen atoms,     -   (n) a cyclic amino group (e.g., 1-piperazinyl, morpholino)         optionally substituted by alkoxycarbonyl,     -   (o) formyl,     -   (p) carbamoyl, and     -   (q) a 5- to 10-membered aromatic heterocyclic group (e.g.,         triazolyl) optionally substituted by alkyl.

More preferably, R³ is a group of the formula

wherein R²² is

-   -   (a) a halogen atom,     -   (b) cyano,     -   (c) nitro,     -   (d) alkyl optionally substituted by 1 to 3 substituents selected         from the group consisting of a halogen atom, alkylamino,         dialkylamino and hydroxy,     -   (e) alkenyl,     -   (f) aryl,     -   (g) cycloalkyl,     -   (h) alkoxy,     -   (i) formyl, or     -   (j) carbamoyl.

Preferably, R² is

-   -   (a) cyano,     -   (b) nitro,     -   (c) aryl,     -   (d) formyl, or     -   (e) carbamoyl.

Preferably, R³ is 5-pyrimidinyl substituted by 1 or 2 substituents selected from the group consisting of amino, alkylamino and dialkylamino.

Preferably, R³ is 2-indolyl, 3-indolyl, 5-indolyl or 6-indolyl, each optionally substituted by 1 or 2 substituents selected from the group consisting of

-   -   (a) a halogen atom,     -   (b) cyano,     -   (c) nitro,     -   (d) hydroxy,     -   (e) alkyl optionally substituted by 1 to 3 substituents selected         from the group consisting of amino, alkoxycarbonylamino,         alkylamino and dialkylamino,     -   (f) alkoxy,     -   (g) formyl,     -   (h) carboxy, and     -   (j) amino optionally substituted by 1 or 2 substituents selected         from the group consisting of         -   (i) alkoxycarbonyl,         -   (ii) alkylcarbonyl optionally substituted by a substituent             selected from the group consisting of             -   (A) cycloalkyloxy optionally substituted by 1 to 3                 alkyl,             -   (B) alkylamino,             -   (C) dialkylamino,             -   (D) a cyclic amino group (e.g., morpholino,                 1-piperazinyl) optionally substituted by alkoxycarbonyl,                 and             -   (E) a halogen atom,         -   (iii) phenylcarbonyl optionally substituted by 1 to 3             substituents selected from the group consisting of alkyl and             alkoxy,         -   (iv) cycloalkylcarbonyl,         -   (v) a 5- to 10-membered aromatic heterocyclylcarbonyl group             (e.g, pyridylcarbonyl) optionally substituted by alkyl             optionally substituted by 1 to 3 halogen atoms,         -   (vi) benzylcarbonyl optionally substituted by 1 to 3             substituents selected from the group consisting of a halogen             atom and alkoxy,         -   (vii) arylsulfonyl optionally substituted by alkoxy,         -   (viii) cycloalkylalkylsulfonyl optionally substituted by 1             to 3 substituents selected from the group consisting of             alkyl and oxo (e.g., camphorsulfonyl),         -   (ix) a 5- to 10-membered aromatic heterocyclylsulfonyl group             (e.g., imidazolylsulfonyl) optionally substituted by 1 to 3             alkyl, and         -   (x) —C(═N—CN)—SR⁹ wherein R⁹ is alkyl.

More preferably, R³ is 2-indolyl optionally substituted by 1 or 2 substituents selected from the group consisting of

-   -   (a) a halogen atom,     -   (b) cyano,     -   (c) nitro,     -   (d) hydroxy,     -   (e) alkyl optionally substituted by 1 to 3 substituents selected         from the group consisting of amino, alkoxycarbonylamino,         alkylamino and dialkylamino,     -   (f) alkoxy,     -   (g) formyl,     -   (h) carboxy, and     -   (j) amino optionally substituted by 1 or 2 substituents selected         from the group consisting of         -   (i) alkoxycarbonyl,         -   (ii) alkylcarbonyl optionally substituted by a substituent             selected from the group consisting of             -   (A) cycloalkyloxy optionally substituted by 1 to 3                 alkyl,             -   (B) alkylamino,             -   (C) dialkylamino,             -   (D) a cyclic amino group (e.g., morpholino,                 1-piperazinyl) optionally substituted by alkoxycarbonyl,                 and             -   (E) a halogen atom,         -   (iii) phenylcarbonyl optionally substituted by 1 to 3             substituents selected from the group consisting of alkyl and             alkoxy,         -   (iv) cycloalkylcarbonyl,         -   (v) a 5- to 10-membered aromatic heterocyclylcarbonyl group             (e.g, pyridylcarbonyl) optionally substituted by alkyl             optionally substituted by 1 to 3 halogen atoms,         -   (vi) benzylcarbonyl optionally substituted by 1 to 3             substituents selected from the group consisting of a halogen             atom and alkoxy,         -   (vii) arylsulfonyl optionally substituted by alkoxy,         -   (viii) cycloalkylalkylsulfonyl optionally substituted by 1             to 3 substituents selected from the group consisting of             alkyl and oxo (e.g., camphorsulfonyl),         -   (ix) a 5- to 10-membered aromatic heterocyclylsulfonyl group             (e.g., imidazolylsulfonyl) optionally substituted by 1 to 3             alkyl, and         -   (x) —C(═N—CN)—SR⁹ wherein R⁹ is alkyl.

Examples of a group of the formula (F) or (G) include a group of the formula

wherein R²³ is a hydrogen atom or alkyl, and R²⁴, R²⁵, R²⁶ and R²⁷ are each independently,

-   -   (a) a hydrogen atom,     -   (b) cyano, or     -   (c) nitro.

Examples of a group of the formula (K) include a group of the formula

wherein X⁵, X⁶, X⁷, X⁸ and R¹⁰ are as defined above.

Preferable examples of a group of the formula (K) include a group of the formula

wherein R¹⁰, R¹¹, R¹², R¹³, R¹⁴ and R¹⁵ are as defined above.

When R¹⁰ and R¹¹ are bonded to form a 5- or 6-membered ring optionally substituted by alkyl or oxo, preferable examples of a group of the formula (K) include a group of the formula

wherein R³¹ is a hydrogen atom or alkyl.

When R¹² and R¹³ are bonded to form a 5- or 6-membered ring, preferable examples of a group of the formula (K) include a group of the formula

More preferable examples of a group of the formula (K) include a group of the formula

wherein R^(10a) is

-   -   (a) a hydrogen atom or     -   (b) alkyl, and         R^(11a), R^(13a) and R^(15a) are each independently,     -   (a) a hydrogen atom,     -   (b) a halogen atom,     -   (c) cyano,     -   (d) nitro,     -   (e) amino,     -   (f) alkylamino,     -   (g) dialkylamino,     -   (h) alkyl optionally substituted by hydroxy, or     -   (i) alkenyl,         R^(10a) and R^(11a) are optionally bonded to form a 5- or         6-membered ring optionally substituted by alkyl or oxo, provided         that R^(10a), R^(11a), R^(13a) and R^(15a) are not         simultaneously hydrogen atom.

Preferably, R³ is a group of the formula

wherein R¹⁶ is

-   -   (a) a hydrogen atom,     -   (b) alkyl optionally substituted by 1 to 3 substituents selected         from the group consisting of cyano, alkylamino and dialkylamino,     -   (c) alkenyl optionally substituted by carboxy,     -   (d) formyl,     -   (e) carboxy,     -   (f) carbamoyl,     -   (g) —C(R¹⁷)═N—OH wherein R¹⁷ is a hydrogen atom, cyano or         hydroxy, or     -   (h) a 5- to 10-membered aromatic heterocyclic group (e.g.,         tetrazolyl, pyrrolyl, oxazolyl, benzimidazolyl, triazolyl)         optionally substituted by alkyl, alkoxycarbonyl, carboxy or         phenyl.

More preferably, R³ is a group of the formula

wherein R^(16a) is

-   -   (a) alkyl optionally substituted by 1 to 3 substituents selected         from the group consisting of cyano, alkylamino and dialkylamino,     -   (b) alkenyl optionally substituted by carboxy,     -   (c) formyl,     -   (d) carboxy,     -   (e) carbamoyl,     -   (f) —C(R¹⁷)═N—OH wherein R¹⁷ is a hydrogen atom, cyano or         hydroxy, or     -   (g) a 5- to 10-membered aromatic heterocyclic group (e.g.,         tetrazolyl, pyrrolyl, oxazolyl, benzimidazolyl, triazolyl)         optionally substituted by alkyl, alkoxycarbonyl, carboxy or         phenyl.

Preferably, R³ is a group of the formula

wherein R¹⁸ is alkyl optionally substituted by 1 to 3 substituents selected from the group consisting of a halogen atom and phenyl, and R¹⁹ and R²⁰ are each independently,

-   -   (a) a hydrogen atom,     -   (b) a halogen atom,     -   (c) cyano,     -   (d) alkyl optionally substituted by 1 to 3 substituents selected         from the group consisting of         -   (i) a halogen atom,         -   (ii) cyano,         -   (iii) hydroxy,         -   (iv) amino,         -   (v) alkylamino,         -   (vi) dialkylamino, and         -   (vii) a cyclic amino group (e.g., 1-piperazinyl) optionally             substituted by alkyl,     -   (e) alkoxy,     -   (f) amino optionally substituted by 1 or 2 substituents selected         from the group consisting of         -   (i) alkylcarbonyl optionally substituted by a cyclic amino             group (e.g., morpholino),         -   (ii) alkylsulfonyl, and         -   (iii) carbamoyl,     -   (g) carboxy,     -   (h) alkoxycarbonyl,     -   (i) carbamoyl optionally substituted by alkyl optionally         substituted by amino, alkylamino, dialkylamino or         alkoxycarbonylamino,     -   (j) formyl,     -   (k) a 5- to 10-membered aromatic heterocyclic group (e.g.,         oxazolyl, benzimidazolyl), or     -   (l) —CH═N—OR²¹ wherein R²¹ is a hydrogen atom or alkyl         optionally substituted by alkylamino or dialkylamino.

More preferably, R³ is a group of the formula

wherein R^(18a) is alkyl, and R^(19a) is (a) a halogen atom,

-   -   (b) cyano,     -   (c) alkyl optionally substituted by 1 to 3 substituents selected         from the group consisting of         -   (i) a halogen atom,         -   (ii) cyano,         -   (iii) hydroxy,         -   (iv) amino,         -   (v) alkylamino,         -   (vi) dialkylamino, and         -   (vii) a cyclic amino group (e.g., 1-piperazinyl) optionally             substituted by alkyl,     -   (d) alkoxy,     -   (e) amino optionally substituted by 1 or 2 substituents selected         from the group consisting of         -   (i) alkylcarbonyl optionally substituted by a cyclic amino             group (e.g., morpholino),         -   (ii) alkylsulfonyl, and         -   (iii) carbamoyl,     -   (f) carboxy,     -   (g) alkoxycarbonyl,     -   (h) carbamoyl optionally substituted by alkyl optionally         substituted by amino, alkylamino, dialkylamino or         alkoxycarbonylamino,     -   (i) formyl,     -   (j) a 5- to 10-membered aromatic heterocyclic group (e.g.,         oxazolyl, benzimidazolyl), or     -   (k) —CH═N—OR²¹ wherein R²¹ is a hydrogen atom or alkyl         optionally substituted by alkylamino or dialkylamino.

Preferable examples of compound (I) are as described below.

[Compound I-1]

A compound of the formula (I) wherein

R is a hydrogen atom; R¹ is cyclopropyl, 2-fluorocyclopropyl or 2,4-difluorophenyl; R² is C₁₋₆ alkyl (e.g., methyl), C₁₋₆ alkoxy (e.g., methoxy) or a chlorine atom; or R¹ and R² are optionally bonded to form —O—CH₂—CH(CH₃)— wherein the oxygen atom is bonded to the phenyl ring of the quinolone ring; and R³ is a fused heterocyclic group of the formula

wherein X¹ is C(R⁵) or N, R⁴ is a hydrogen atom or C₁₋₆ alkyl, and R⁵ is (a) a hydrogen atom,

-   -   (b) a halogen atom,     -   (c) cyano,     -   (d) nitro,     -   (e) hydroxy,     -   (f) C₁₋₆ alkyl optionally substituted by 1 to 3 halogen atoms,     -   (g) C₂₋₆ alkynyl,     -   (h) C₆₋₁₄ aryl, or     -   (i) C₁₋₆ alkoxy optionally substituted by 1 to 3 halogen atoms,         when X¹ is C(R⁵), R⁴ and R⁵ are optionally bonded to form         —CH₂—O—(C═O)— wherein the carbonyl is bonded to the phenyl ring         of the quinolone ring,         said fused heterocyclic group is optionally substituted by 1 or         2 substituents selected from the group consisting of a halogen         atom, cyano, nitro, hydroxy and C₁₋₆ alkyl,         or a salt thereof.

[Compound I-2]

A compound of the formula (I) wherein

R is a hydrogen atom; R¹ is cyclopropyl, 2-fluorocyclopropyl or 2,4-difluorophenyl; R² is C₁₋₆ alkyl (e.g., methyl), C₂₋₆ alkoxy (e.g., methoxy) or a chlorine atom; or R¹ and R² are optionally bonded to form —O—CH₂—CH(CH₃)— wherein the oxygen atom is bonded to the phenyl ring of the quinolone ring; and R³ is a group of the formula

wherein

X is C(R⁸) or N, and

R⁶, R⁷ and R⁸ are each independently,

-   -   (a) a hydrogen atom,     -   (b) a halogen atom,     -   (c) cyano,     -   (d) nitro,     -   (e) amino,     -   (f) C₁₋₆ alkyl optionally substituted by 1 to 3 substituents         selected from the group consisting of a halogen atom and amino,     -   (g) C₂₋₆ alkenyl,     -   (h) C₂₋₆ alkynyl,     -   (i) C₆₋₁₄ aryl,     -   (j) formyl,     -   (k) carboxy,     -   (l) carbamoyl, or     -   (m) a 5- to 10-membered aromatic heterocyclic group (e.g.,         pyridyl, triazolyl) optionally substituted by C₁₋₆ alkyl,         or a salt thereof.

[Compound I-3]

A compound of the formula (I) wherein

R is a hydrogen atom; R¹ is cyclopropyl, 2-fluorocyclopropyl or 2,4-difluorophenyl; R² is C₁₋₆ alkyl (e.g., methyl), C₁₋₆ alkoxy (e.g., methoxy) or a chlorine atom; and R³ is a group of the formula

wherein X³ and X⁴ are N, or X³ is N and X⁴ is CH, or X³ is CH and X⁴ is N, and R⁶ is a hydrogen atom, a halogen atom, nitro or amino, or a salt thereof.

[Compound I-4]

A compound of the formula (I) wherein

R is a hydrogen atom; R¹ is cyclopropyl, 2-fluorocyclopropyl or 2,4-difluorophenyl; R² is C₁₋₆ alkyl (e.g., methyl), C₁₋₆ alkoxy (e.g., methoxy) or a chlorine atom; and R³ is a group of the formula

or a salt thereof.

[Compound I-5]

A compound of the formula (i) wherein

R is a hydrogen atom; R¹ is cyclopropyl, 2-fluorocyclopropyl or 2,4-difluorophenyl; R² is C₁₋₆ alkyl (e.g., methyl), C₁₋₆ alkoxy (e.g., methoxy) or a chlorine atom; or R¹ and R² are optionally bonded to form —CH₂—CH(CH₃)— wherein the oxygen atom is bonded to the phenyl ring of the quinolone ring; and R³ is a group of the formula

wherein R²² is

-   -   (a) a halogen atom,     -   (b) cyano,     -   (c) nitro,     -   (d) C₁₋₆ alkyl optionally substituted by 1 to 3 substituents         selected from the group consisting of a halogen atom, C₁₋₆         alkylamino, di(C₁₋₆ alkyl) amino and hydroxy,     -   (e) C₂₋₆ alkenyl,     -   (f) C₆₋₁₄ aryl,     -   (g) C₃₋₈ cycloalkyl,     -   (h) C₁₋₆ alkoxy,     -   (i) formyl, or     -   (j) carbamoyl,         or a salt thereof.

[Compound I-6]

A compound of the formula (I) wherein

R is a hydrogen atom; R¹ is cyclopropyl, 2-fluorocyclopropyl or 2,4-difluorophenyl; R² is C₁₋₆ alkyl (e.g., methyl), C₁₋₆ alkoxy (e.g., methoxy) or a chlorine atom; or R¹ and R² are optionally bonded to form —CH₂—CH(CH₃)— wherein the oxygen atom is bonded to the phenyl ring of the quinolone ring; and R³ is a group of the formula

wherein R²³ is

-   -   (a) cyano,     -   (b) nitro,     -   (c) C₆₋₁₄ aryl,     -   (d) formyl, or     -   (e) carbamoyl,         or a salt thereof.

[Compound I-7]

A compound of the formula (I) wherein

R is a hydrogen atom; R¹ is cyclopropyl, 2-fluorocyclopropyl or 2,4-difluorophenyl; R² is C₁₋₆ alkyl (e.g., methyl), C₁₋₆ alkoxy (e.g., methoxy) or a chlorine atom; and R³ is 5-pyrimidinyl substituted by 1 or 2 substituents selected from the group consisting of amino, C₁₋₆ alkylamino and di(C₁₋₆ alkyl)amino, or a salt thereof.

[Compound I-8]

A compound of the formula (I) wherein

R is a hydrogen atom; R¹ is cyclopropyl, 2-fluorocyclopropyl or 2,4-difluorophenyl; R² is C₁₋₆ alkyl (e.g., methyl), C₁₋₆ alkoxy (e.g., methoxy) or a chlorine atom; and R³ is 2-indolyl optionally substituted by 1 or 2 substituents selected from the group consisting of

-   -   (a) a halogen atom,     -   (b) cyano,     -   (c) nitro,     -   (d) hydroxy,     -   (e) C₁₋₆ alkyl optionally substituted by 1 to 3 substituents         selected from the group consisting of amino, C₁₋₆         alkoxy-carbonylamino, C₁₋₆ alkylamino and di(C₁₋₆ alkyl) amino,     -   (f) C₁₋₆ alkoxy,     -   (g) formyl,     -   (h) carboxy, and     -   (j) amino optionally substituted by 1 or 2 substituents selected         from the group consisting of         -   (i) C₁₋₆ alkoxy-carbonyl,         -   (ii) C₁₋₆ alkyl-carbonyl optionally substituted by a             substituent selected from the group consisting of             -   (A) C₃₋₈ cycloalkyloxy optionally substituted by 1 to 3                 C₁₋₆ alkyl,             -   (B) C₁₋₆ alkylamino,             -   (C) di(C₁₋₆ alkyl)amino,             -   (D) a cyclic amino group (e.g., morpholino,                 1-piperazinyl) optionally substituted by C₁₋₆                 alkoxy-carbonyl, and             -   (E) a halogen atom,         -   (iii) phenylcarbonyl optionally substituted by 1 to 3             substituents selected from the group consisting of C₁₋₆             alkyl and C₁₋₆ alkoxy,         -   (iv) C₃₋₈ cycloalkyl-carbonyl,         -   (v) a 5- to 10-membered aromatic heterocyclylcarbonyl group             (e.g., pyridylcarbonyl) optionally substituted by C₁₋₆ alkyl             optionally substituted by 1 to 3 halogen atoms,         -   (vi) benzylcarbonyl optionally substituted by 1 to 3             substituents selected from the group consisting of a halogen             atom and C₁₋₆ alkoxy,         -   (vii) C₆₋₁₄ arylsulfonyl optionally substituted by C₁₋₆             alkoxy,         -   (viii) C₃₋₈ cycloalkyl-C₁₋₆ alkylsulfonyl optionally             substituted by 1 to 3 substituents selected from the group             consisting of C₁₋₆ alkyl and oxo (e.g., camphorsulfonyl),         -   (ix) a 5- to 10-membered aromatic heterocyclylsulfonyl group             (e.g., imidazolylsulfonyl) optionally substituted by 1 to 3             C₁₋₆ alkyl, and         -   (x) —C(═N—CN)—SR⁹ wherein R⁹ is C₁₋₆ alkyl, or a salt             thereof.

[Compound I-9]

A compound of the formula (I) wherein

R is a hydrogen atom; R¹ is cyclopropyl, 2-fluorocyclopropyl or 2,4-difluorophenyl; R² is C₁₋₆ alkyl (e.g., methyl), C₁₋₆ alkoxy (e.g., methoxy) or a chlorine atom; and R³ is a group of the formula

wherein R² is a hydrogen atom or C₁₋₆ alkyl, and R²⁴, R²⁵, R²⁶ and R²⁷ are each independently,

-   -   (a) a hydrogen atom,     -   (b) cyano, or     -   (c) nitro,         or a salt thereof.

[Compound I-10]

A compound of the formula (I) wherein

R is a hydrogen atom; R¹ is cyclopropyl, 2-fluorocyclopropyl or 2,4-difluorophenyl; R² is C₁₋₆ alkyl (e.g., methyl), C₁₋₆ alkoxy (e.g., methoxy) or a chlorine atom; and R³ is a group of the formula

wherein R²⁶ is a hydrogen atom or hydroxy, and R²⁹ is a hydrogen atom or C₁₋₆ alkyl, or a salt thereof.

[Compound I-11]

A compound of the formula (I) wherein

R is a hydrogen atom; R¹ is cyclopropyl, 2-fluorocyclopropyl or 2,4-difluorophenyl; R² is C₁₋₆ alkyl (e.g., methyl), C₁₋₆ alkoxy (e.g., methoxy) or a chlorine atom; and R³ is a group of the formula

wherein R¹⁰, R¹² and R¹⁴ are each independently,

-   -   (a) a hydrogen atom or     -   (b) C₁₋₆ alkyl, and         R¹¹, R¹³ and R¹⁵ are each independently,     -   (a) a hydrogen atom,     -   (b) a halogen atom,     -   (c) cyano,     -   (d) nitro,     -   (e) amino,     -   (f) C₁₋₆ alkylamino,     -   (g) di(C₁₋₆ alkyl) amino,     -   (h) C₁₋₆ alkyl optionally substituted by hydroxy, or     -   (i) C₂₋₆ alkenyl, or         R¹⁰ and R¹¹ are optionally bonded to form —(C═O)—NH—, —C(R³¹)—N—         or —N═N— wherein R³¹ is a hydrogen atom or C₁₋₆ alkyl, and the         nitrogen atom is bonded to the phenyl ring of the fused ring, or         R¹² and R¹³ are optionally bonded to form —(CH₂)₄—,         or a salt thereof.

[Compound I-12]

A compound of the formula (I) wherein

R is a hydrogen atom; R¹ is cyclopropyl, 2-fluorocyclopropyl or 2,4-difluorophenyl; R² is C₁₋₆ alkyl (e.g., methyl), C₁₋₆ alkoxy (e.g., methoxy) or a chlorine atom; and R³ is a group of the formula

wherein R^(10a) is

-   -   (a) a hydrogen atom or     -   (b) C₁₋₆ alkyl, and         R^(11a), R^(13a) and R^(15a) are each independently,     -   (a) a hydrogen atom,     -   (b) a halogen atom,     -   (c) cyano,     -   (d) nitro,     -   (e) amino,     -   (f) C₁₋₆ alkylamino,     -   (g) di(C₁₋₆ alkyl) amino,     -   (h) C₁₋₆ alkyl optionally substituted by hydroxy, or     -   (i) C₂₋₆ alkenyl, and         provided that R^(10a), R^(11a), R^(13a) and R^(15a) are not         simultaneously hydrogen atom,         or a salt thereof.

[Compound I-13]

A compound of the formula (I) wherein

R is a hydrogen atom; R¹ is cyclopropyl, 2-fluorocyclopropyl or 2,4-difluorophenyl; R² is C₁₋₆ alkyl (e.g., methyl), C₁₋₆ alkoxy (e.g., methoxy) or a chlorine atom; and R³ is a group of the formula

wherein R³¹ is a hydrogen atom or C₁₋₆ alkyl, or a salt thereof.

[Compound T-14]

A compound of the formula (I) wherein

R is a hydrogen atom; R¹ is cyclopropyl, 2-fluorocyclopropyl or 2,4-difluorophenyl; R² is C₁₋₆ alkyl (e.g., methyl), C₁₋₆ alkoxy (e.g., methoxy) or a chlorine atom; and R³ is a group of the formula

wherein R^(16a)

-   -   (a) C₁₋₆ alkyl optionally substituted by 1 to 3 substituents         selected from the group consisting of cyano, C₁₋₆ akylamino and         di(C₁₋₆ alkyl) amino,     -   (b) C₂₋₆ alkenyl optionally substituted by carboxy,     -   (c) formyl,     -   (d) carboxy,     -   (e) carbamoyl,     -   (f) —C(R¹⁷)═N—OH wherein R¹ is a hydrogen atom, cyano or         hydroxy, or     -   (g) a 5- to 10-membered aromatic heterocyclic group (e.g.,         tetrazolyl, pyrroryl, oxazolyl, benzimidazolyl, triazolyl)         optionally substituted by C₁₋₆ alkyl, C₁₋₆ alkoxy-carbonyl,         carboxy or phenyl,         or a salt thereof.

[Compound I-15]

A compound of the formula (I) wherein

R is a hydrogen atom; R¹ is cyclopropyl, 2-fluorocyclopropyl or 2,4-difluorophenyl; R² is C₁₋₆ alkyl (e.g., methyl), C₁₋₆ alkoxy (e.g., methoxy) or a chlorine atom; and R³ is a group of the formula

wherein R^(16a) is C₁₋₆ alkyl, and R^(19a) is (a) a halogen atom,

-   -   (b) cyano,     -   (c) C₁₋₆ alkyl optionally substituted by 1 to 3 substituents         selected from the group consisting of         -   (i) a halogen atom,         -   (ii) cyano,         -   (iii) hydroxy,         -   (iv) amino,         -   (v) C₆ alkylamino,         -   (vi) di(C₁₋₆ alkyl) amino, and         -   (vii) a cyclic amino group (e.g., 1-piperazinyl) optionally             substituted by C₁₋₆ alkyl,     -   (d) C₁₋₆ alkoxy,     -   (e) amino optionally substituted by 1 or 2 substituents selected         from the group consisting of         -   (i) C₁₋₆ alkyl-carbonyl optionally substituted by a cyclic             amino group (e.g., morpholino),         -   (ii) C₁₋₆ alkylsulfonyl, and         -   (iii) carbamoyl,     -   (f) carboxy,     -   (g) C₁₋₆ alkoxy-carbonyl,     -   (h) carbamoyl optionally substituted by C₁₋₆ alkyl optionally         substituted by amino, C₁₋₆ alkylamino, di(C₁₋₆ alkyl)amino or         C₁₋₆ alkoxy-carbonylamino,     -   (i) formyl,     -   (j) a 5- to 10-membered aromatic heterocyclic group (e.g.,         oxazolyl, benzimidazolyl), or     -   (k) —CH═N—OR²¹ wherein R²¹ is a hydrogen atom or C₁₋₆ alkyl         optionally substituted by C₁₋₆ alkylamino or di(C₁₋₆         alkyl)amino,         or a salt thereof.

[Compound I-16]

A compound of the formula (I) wherein

R is a hydrogen atom; R¹ is cyclopropyl, 2-fluorocyclopropyl or 2,4-difluorophenyl; R² is C₁₋₆ alkyl (e.g., methyl), C₁₋₆ alkoxy (e.g., methoxy) or a chlorine atom; and R³ is a group of the formula

wherein R³⁰ is (a) a hydrogen atom,

-   -   (b) a halogen atom,     -   (c) cyano,     -   (d) C₁₋₆ alkyl optionally substituted by 1 to 3 substituents         selected from the group consisting of a halogen atom and         hydroxy,     -   (e) C₂₋₆ alkenyl,     -   (f) C₂₋₆ alkynyl,     -   (g) C₁₋₆ alkoxy,     -   (h) formyl, or     -   (i) —CH═N—OH,         or a salt thereof.

Examples of salts of the compound of the formula (I) include pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compound of the formula (I) are conventional non-toxic salts and include, for example, a salt with a base or an acid addition salt such as a salt with an inorganic base, for example, an alkali metal salt (e.g., sodium salt, potassium salt, etc.), an alkaline earth metal salt (e.g., calcium salt, magnesium salt, etc.), an ammonium salt; a salt with an organic base, for example, an organic amine salt (e.g., trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N′-dibenzylethylenediamine salt, etc.); an inorganic acid addition salt (e.g., hydrochloride, hydrobromide, sulfate, hydrogensulfate, phosphate, etc.); an organic carboxylic or sulfonic acid addition salt (e.g., formate, acetate, trifluoroacetate, maleate, tartrate, citrate, fumarate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.); and a salt with a basic or acidic amino acid (e.g., arginine, aspartic acid, glutamic acid, etc.).

Compound (I) can be produced, for example, by a method according to the following reaction schemes.

wherein X, R¹ and R² are as defined above, R³² is alkyl and R³³ is alkyl.

Step a

Compound (1) can be converted to acid halide by reacting compound (1) with a halogenating agent in the presence or absence of a solvent. The solvent includes aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as dichloromethane, chloroform and carbon tetrachloride; ethers such as dioxane, tetrahydrofuran and diethyl ether; N,N-dimethylformamide (DMF); dimethyl sulfoxide (DMSO); and the like. The halogenating agent may be any conventional halogenating agents which can convert hydroxy in carboxy group into a halogen atom, and includes, for example, thionyl chloride, phosphorus oxychloride, phosphorus oxybromide, phosphorus pentachloride, phosphorus pentabromide, and the like. The amounts of compound (1) and the halogenating agent are not particularly limited, but, in case of using no solvent, the halogenating agent is usually used in a large excess amount, and in case of using a solvent, the halogenating agent is usually used in an amount of at least 1 mole, preferably 2 to 4 moles, per 1 mole of compound (1). The reaction temperature and the reaction period of time are not particularly limited, but the reaction is usually carried out at a temperature of from room temperature to about 100° C. for about 30 minutes to about 6 hours.

The obtained acid halide is reacted with magnesium salt of malonic acid monoalkyl ester to give compound (2). Magnesium salt of malonic acid monoalkyl ester can be prepared in situ from potassium salt of malonic acid monoalkyl ester such as potassium ethyl malonate in the presence of magnesium chloride and a basic compound such as triethylamine. The reaction can be carried out in a suitable solvent. The solvent used in the reaction may be any conventional solvents unless they give any undesirable effect on the reaction, and includes, for example, esters such as ethyl acetate; ethers such as diethyl ether, dioxane, tetrahydrofuran, monoglyme and diglyme; alcohols such as methanol, ethanol and isopropanol; aromatic hydrocarbons such as benzene, toluene and xylene; aliphatic hydrocarbons such as n-hexane, heptane, cyclohexane and ligroin; amines such as pyridine and N,N-dimethylaniline; halogenated hydrocarbons such as chloroform, dichloromethane and carbon tetrachloride; aprotic polar solvents such as DMF, DMSO and hexamethylphosphoric triamide (HMPA); and a mixture of these solvents. The reaction is usually carried out at a temperature of from about 0° C. to about 150° C., preferably from about 0° C. to about 120° C., for about 0.5 to about 20 hours. Potassium salt of malonic acid monoalkyl ester is usually used in an amount of at least 1 mole, preferably 1 to 2 moles, per 1 mole of compound (1). Magnesium chloride and the basic compound are usually used in an amount of at least 1 mole, preferably 1 to 2 moles, per 1 mole of compound (1).

Step b

Compound (3) can be prepared by reacting compound (2) with trialkyl orthoformate such as trimethyl orthoformate and triethyl orthoformate in acetic anhydride. The reaction s usually carried out at a temperature of from about 0° C. to about 200° C., preferably from about 0° C. to about 150° C., for about 0.5 to about 20 hours. Trialkyl orthoformate is usually used in an amount of at least 1 mole, preferably 1 to 10 moles, per 1 mole of compound (2).

Step c

Compound (4) can be prepared by reacting compound (3) with compound (6).

The reaction between compound (3) and compound (6) can be carried out in a suitable solvent. The solvent employed in the reaction may be any conventional solvents unless they give any undesirable effect on the reaction, and includes, for example, alcohols such as methanol, ethanol and propanol; ethers such as diethyl ether, dioxane, tetrahydrofuran, monoglyme and diglyme; aromatic hydrocarbons such as benzene, toluene and xylene; aliphatic hydrocarbons such as n-hexane, heptane, cyclohexane and ligroin; halogenated hydrocarbons such as chloroform, methylene chloride and carbon tetrachloride; aprotic polar solvents such as DMF, DMSO and HMPA; and the like. The reaction is usually carried out at a temperature of from about 0° C. to about 150° C., preferably from room temperature to about 100° C., for about 0.1 to about 15 hours. Compound (6) is usually used in an amount of at least 1 mole, preferably 1 to 2 moles, per 1 mole of compound (3).

Step d

Compound (5) can be prepared by cyclization of compound (4).

The cyclization of compound (4) can be carried out in a suitable solvent in the presence of a basic compound. The solvent employed in the reaction may be any conventional solvents unless they give any undesirable effect on the reaction, and includes, for example, ethers such as diethyl ether, dioxane, tetrahydrofuran, monoglyme and diglyme; aliphatic hydrocarbons such as n-hexane, heptane and ligroin; halogenated hydrocarbons such as chloroform, methylene chloride and carbon tetrachloride; aprotic polar solvents such as DF, DMSO and HMPA; and the like. The basic compound employed in the reaction includes inorganic bases such as metallic sodium, metallic potassium, sodium hydride, sodium amide, sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate, metal alcoholates such as sodium methylate and sodium ethylate, organic bases such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), N-benzyltrimethylammonium hydroxide and tetrabutylammonium hydroxide, and the like. The reaction is usually carried out at a temperature of from about 0° C. to about 200° C., preferably from room temperature to about 150° C., for about 0.5 to about 15 hours. The basic compound is usually used in an amount of at least 1 mole, preferably 1 to 2 moles, per 1 mole of the compound (4).

wherein X, R¹, R², R³ and R³² are as defined above.

Step a

Compound (Ia) can be prepared by reacting compound (5) and compound (7) or compound (8) in an inert solvent or without using any solvents, in the presence or absence of a basic compound, in the presence of a palladium catalyst.

Examples of inert solvents include water; ethers such as dioxane, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, diethylene glycol dimethyl ether and ethylene glycol dimethyl ether; aromatic hydrocarbons such as benzene, toluene and xylene; alcohols such as methanol, ethanol and isopropanol; ketones such as acetone and methyl ethyl ketone; and aprotic polar solvents such as DMF, DMSO, HMPA and acetonitrile. These inert solvents can be used singly or in combinations of two or more.

The palladium catalyst used in the reaction is not particularly limited, but include, for example, tetravalent palladium catalysts such as sodium hexachloropalladate(IV) tetrahydrate and potassium hexachloropalladate(IV); divalent palladium catalysts such as palladium(II) chloride, palladium(II) bromide, palladium(TT) acetate, palladium(II) acetylacetonate, dichlorobis(benzonitrile)palladium(II), dichlorobis(acetonitrile)palladium(IT), dichlorobis(triphenylphosphine)palladium(II), dichlorotetramine palladium (II), dichloro(cycloocta-1,5-diene) palladium (II), palladium(II) trifluoroacetate, and 1,1′-bis(diphenylphosphino)ferrocene dichloropalladium(II) dichloromethane complex (Pd(dppf)Cl₂.CH₂Cl₂); zerovalent palladium catalysts such as tris(dibenzylideneacetone)dipalladium(0), tris(dibenzylideneacetone)dipalladium(0) chloroform complex and tetrakis(triphenylphosphine)palladium (0), etc. These palladium catalysts are used singly or in combinations of two or more.

In the reaction, the amount of the palladium catalyst is not particularly limited, but is typically in the range from 0.000001 to 20 moles in terms of palladium relative to 1 mole of compound (5). The amount of the palladium catalyst is preferably in the range from 0.0001 to 5 moles in terms of palladium relative to 1 mole of compound (5).

This reaction advantageously proceeds in the presence of a suitable ligand. Examples of ligands of the palladium catalyst include, for example, 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP), tri-o-tolylphosphine, bis(diphenylphosphino)ferrocene, triphenylphosphine, tri-t-butylphosphine and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos). These ligands are used singly or in combinations of two or more.

The proportion of the palladium catalyst and ligand is not particularly limited. The amount of the ligand is about 0.1 to about 100 moles per 1 mole of the palladium catalyst, and preferably about 0.5 to about 15 moles per 1 mole of the palladium catalyst.

Various known inorganic and organic bases can be used as basic compounds.

Inorganic bases include, for example, alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, cesium hydroxide and lithium hydroxide; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate and lithium carbonate; alkali metal hydrogen carbonates such as lithium hydrogen carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate; alkali metals such as sodium and potassium; phosphates such as sodium phosphate and potassium phosphate; amides such as sodium amide; and alkali metal hydrides such as sodium hydride and potassium hydride.

Organic bases include, for example, alkali metal lower alkoxides such as sodium methoxide, sodium ethoxide, sodium t-butoxide, potassium methoxide, potassium ethoxide and potassium t-butoxide, and amines such as triethylamine, tripropylamine, pyridine, quinoline, piperidine, imidazole, N-ethyldiisopropylamine, dimethylaminopyridine, trimethylamine, dimethylaniline, N-methylmorpholine, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO), etc.

Such basic compounds can be used singly or in combinations of two or more. More preferable basic compounds used in the reaction include alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate and lithium carbonate.

The basic compound is usually used in an amount of 0.5 to 10 moles per 1 mole of compound (5), and preferably 0.5 to 6 moles per 1 mole of compound (5).

Compound (7) or compound (8) is usually used in an amount of at least 1 mole per 1 mole of compound (5), and preferably about 1 to about 5 moles per 1 mole of compound (5).

The reaction can be conducted under normal pressure, under inert gas atmosphere including nitrogen, argon, etc., or under increased pressure.

The reaction proceeds usually from room temperature to about 200° C., and preferably from room temperature to about 150° C., and is usually completed in about 1 to about 30 hours. The reaction is also achieved by heating at about 100° C. to about 200° C. for about 5 minutes to about 1 hour using a microwave reactor.

Step b

Compound (Ib) can be prepared by hydrolysis of compound (Ia).

The hydrolysis of compound (Ia) can be carried out under the conditions of conventional hydrolysis, for example, in the presence of a basic compound such as sodium hydroxide, potassium hydroxide, barium hydroxide or potassium carbonate; a mineral acid such as sulfuric acid, hydrochloric acid or nitric acid; or an organic acid such as acetic acid or an aromatic sulfonic acid, in a solvent including water, alcohols such as methanol, ethanol and isopropanol; ketones such as acetone and methyl ethyl ketone; ethers such as dioxane and ethylene glycol diethyl ether; acetic acid; or a mixture thereof. The reaction is usually carried out at a temperature of from room temperature to about 200° C., preferably from room temperature to about 150° C., for about 0.1 to about 30 hours.

Reaction Scheme III Preparation of Boronate and Boronic Acid

wherein R³ is as defined above, and Z is a bromine atom or an iodine atom.

Step a

Compound (7) can be prepared by reacting compound (9) with bis(pinacolato)diboron (10) in an inert solvent in the presence of a palladium catalyst and a basic compound.

Examples of inert solvents and palladium catalyst are same as those described in Step a in Reaction Scheme II.

The basic compound employed in the reaction includes potassium acetate, triethylamine, N-methylmorpholin, sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate, potassium phosphate and sodium hydrogen carbonate.

In the reaction, the amount of the palladium catalyst is not particularly limited, but is typically in the range from 0.000001 to 20 moles in terms of palladium relative to 1 mole of compound (9). The amount of the palladium catalyst is preferably in the range from 0.0001 to 5 moles in terms of palladium relative to 1 mole of compound (9).

The basic compound is usually used in an amount of 0.5 to 10 moles per 1 mole of compound (9), and preferably 0.5 to 6 moles per 1 role of compound (9).

Bis(pinacolato)diboron (10) is usually used in an amount of at least 1 mole per 1 mole of compound (9), and preferably about 1 to about 5 moles per 1 mole of compound (9).

The reaction can be conducted under normal pressure, under inert gas atmosphere including nitrogen, argon, etc., or under increased pressure.

The reaction proceeds usually from room temperature to about 200° C., and preferably from room temperature to about 150° C., and is usually completed in about 1 to about 30 hours.

Step b

Compound (8) can be prepared by reacting compound (9) with trialkyl borate such as trimethyl borate, triethyl borate, tri(isopropyl) borate and tri(n-butyl) borate in an inert solvent in the presence of n-butyllithium or lithium diisopropylamide.

Examples of inert solvents are same as those described in Step a in Reaction Scheme II.

The trialkyl borate is usually used in an amount of at least 1 mole per 1 mole of compound (9), and preferably about 1 to about 5 moles per 1 mole of compound (9).

n-Butyllithium or lithium diisopropylamide is usually used in an amount of at least 1 mole per 1 mole of compound (9), and preferably about 1 to about 5 moles per 1 mole of compound (9).

The reaction is usually carried out at a temperature of from about −70° C. to about 0° C. for about 0.1 to about 15 hours.

Compound (I) of the present invention can easily be converted into a salt thereof by treating with a pharmaceutically acceptable acid or base. The acid includes inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid and hydrobromic acid and organic acids such as oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, benzoic acid, lactic acid, methanesulfonic acid and propionic acid. The base includes sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium hydrogen carbonate, and the like.

The compound thus obtained can easily be isolated and purified by conventional methods, such as, for example, extraction with solvents, dilution method, recrystallization, column chromatography and preparative thin layer chromatography.

Compound (I) shows an excellent antimicrobial activity against mycoplasma, Pseudomonas aeruginosa, anaerobic bacteria, resistant cells against various antimicrobials, clinically isolated bacteria, and gram negative and gram positive bacteria such as Clostridium difficile, Enterococcus faecalis and Staphylococcus pyogenes and hence is useful as an antimicrobial agent for the treatment of diseases induced by these microorganisms. Compound (I) also shows low toxicity and less side effects and is characteristic in good absorbability and in sustained activity.

Since compound (I) shows an excellent antimicrobial activity against Clostridium difficile, it is useful for the prevention or treatment of intestinal infections including antibiotics-associated diarrhea (AAD) such as Clostridium difficile-associated diarrhea (CDAD).

The compounds of the present invention are usually used in the form of a usual pharmaceutical preparation. The pharmaceutical preparation can be prepared in admixture with conventional pharmaceutically acceptable diluents or carriers, such as fillers, bulking agents, binding agents, wetting agents, disintegrators, surfactants and lubricating agents. The pharmaceutical preparation includes various preparations suitable for treatment of the diseases, for example, tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories, injections such as solutions and suspensions, and the like. In the preparation of tablets, there may be used any conventional carriers, for example, excipients such as lactose, white sugar, sodium chloride, glucose, urea, starches, calcium carbonate, kaolin, crystalline cellulose and silicate, binding agents such as water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose, potassium phosphate and polyvinylpyrrolidone, disintegrators such as dry starch, sodium alginate, agar powder, laminaran powder, sodium hydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic monoglyceride, starches and lactose, disintegration inhibitors such as white sugar, stearin, cacao butter and hydrogenated oils, absorption promoters such as quaternary ammonium salts and sodium lauryl sulfate, wetting agents such as glycerin and starches, adsorbents such as starches, lactose, kaolin, bentonite and colloidal silicates, lubricants such as purified talc, stearates, boric acid powder and polyethylene glycol, and the like. The tablets may also be coated with conventional coating agents, for example, may be in the form of a sugar coated tablet, a gelatin-coated tablets, an enteric coating tablet, a film coating tablet, or a double or multiple layers tablet. In the preparation of pills, there may be used conventional carriers, including excipients such as glucose, lactose, starches, cacao butter, hydrogenated vegetable oils, kaolin and talc, binding agents such as gum arabic powder, tragacanth powder, gelatin and ethanol, disintegrators such as laminaran and agar, and the like. In the preparation of suppositories, there may be used conventional carriers, such as, for example, polyethylene glycol, cacao butter, higher alcohols, higher alcohol esters, gelatin and semi-synthesized glycerides. In the preparation of injections, the solutions, emulsions or suspensions of the compounds are sterilized and are preferably made isotonic with the body liquid. These solutions, emulsions and suspensions are prepared by admixing the active compound with a conventional diluent, such as water, aqueous lactic acid solution, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol or polyoxyethylene sorbitan fatty acid esters. The preparations may also be incorporated with sodium chloride, glucose or glycerin in an amount sufficient to make them isotonic with the body liquid. The preparations may also be incorporated with conventional solubilizers, buffering agents, anesthetizing agents, and further, with coloring agents, preservatives, perfumes, flavors, sweetening agents, and other medicaments. The preparations in the form of a paste, cream or gel may be prepared by using as a diluent such as white petrolatum, paraffin, glycerin, cellulose derivatives, polyethylene glycol, silicone, bentonite, or the like. When the compound of the active ingredient precipitates in the injection, an acid such as, for example, methanesulfonic acid, propionic acid, hydrochloric acid, succinic acid or lactic acid may be added to the injection as required to preserve the injection in a stable solution.

Compound (I) may be contained in any amount in the preparations, and are usually contained in an amount of from 1 to 70% by weight based on the whole weight of the preparations.

The pharmaceutical preparations of the present invention can be administered in any methods. Suitable method for administration may be selected in accordance with the preparation form, age and sex of patients, severity of the diseases, and the like. For instance, tablets, pills, solutions, suspensions, emulsions, granules and capsules are administered in oral route. In case of injection, it is administered intravenously in a single form or together with an auxiliary liquid such as glucose or amino solution. The injections may also be administered in intramuscular, intracutaneous, subcutaneous, or intraperitoneal route. Suppositories are administered in intrarectal route.

The dosage of the pharmaceutical preparations of the present invention may vary according to administration methods, age and sex of patients, severity of the diseases, and the like, usually in the range of about 0.1 to about 100 mg, more preferably in the range of about 0.1 to about 50 mg, of compound (I) per 1 kg body weight of the patient per day. The preparation is usually administered by dividing into 2 to 4 times per day.

The present invention is illustrated by the following Examples, Experimental Examples and Preparation Examples. It is to be understood that the present invention is not limited to these Examples, Experimental Examples or Preparation Examples and various changes and modifications can be made without departing from the scope and spirit of the present invention.

EXAMPLES

In our work, Suzuki coupling was employed as key reaction to construct our final products. For the coupling, the corresponding iodo-intermediates could be prepared through well-known methods that were wildly used to synthesis of quinolones before (General Scheme I).

Example 1: Synthesis of Intermediate 5a (R²=Me)

1.1. Compound 2: A mixture of compound 1 (2 g, 6.71 mmol) and thionyl chloride (9.8 mL) was refluxed for 3 hr, and then concentrated to give acid chloride. To the residue was added dry EtOAc (10 mL) and then the mixture was concentrated.

A mixture of potassium ethyl malonate (1.6 g, 9.40 mmol) and MgCl₂ (1.91 g, 20.13 mmol) in dry EtOAc was stirred for 30 min below 50° C. To the mixture was added Et₃N (2.83 mL, 20.13 mmol) below 50° C. Then, the mixture was refluxed for 1 hr. To the mixture was added dropwise a solution of the acid chloride in dry EtOAc (10 mL) at 50-70° C. and then the mixture was refluxed for 1.5 hr. Water (30 mL) and 5 N HCl (30 mL) were added to the reaction mixture under ice-cooling. The EtOAc solution was washed with water, dried and concentrated to give compound 2 as a yellow oil, which was used in the next step without purification.

1.2. Compound 3: A mixture of compound 2 (11 g, 29.88 mmol), triethyl orthoformate (7.47 mL, 44.82 mmol) and acetic anhydride (6.77 mL, 71.72 mmol) was heated at 150° C. for 1 hr, and then concentrated to give compound 3, which was used in the next step without purification. 1.3. Compound 4: To compound 3 (obtained above) were added EtOH (50 mL) and cyclopopylamine (2.48 mL, 35.86 mmol). The mixture was stirred for 30 min and concentrated to give compound 4, which was used in the next step without purification. 1.4. Intermediate 5a: Compound 4 (obtained above) was dissolved in dry DMSO (100 mL). K₂CO₃ (16.52 g, 119.53 mmol) was added to the solution. The reaction mixture was stirred at 100° C. for 1 hr. When TLC (EtOAc/dipropyl ether=1/1) indicated the reaction was completed, the mixture was cooled to room temperature, poured into water, and extracted with EtOAc. The organic layer was washed with brine, dried and concentrated to give a yellow solid which was recrystallized from EtOAc. Intermediate 5a was obtained as a white solid in 75% overall yield. ¹H NMR (400 MHz, DMSO) δ 8.60 (s, 1H), 7.70 (d, J=7.8 Hz, 1H), 4.29-4.14 (m, 3H), 2.96 (s, 3H), 1.28 (t, J=7.1 Hz, 3H), 1.14 (q, J=7.0 Hz, 2H), 0.87-0.76 (m, 2H).

The following compounds were synthesized according to General Scheme I.

Example 2

Intermediate 5b (R²═OMe): ¹H NMR (400 MHz, DMSO) δ 8.51 (s, 1H), 7.69 (d, J=7.7 Hz, 1H), 4.23 (dd, J=14.0, 6.9 Hz, 2H), 4.03 (s, 1H), 3.80 (s, 3H), 1.28 (t, J=7.0 Hz, 3H), 1.09 (d, J=6.2 Hz, 2H), 0.97 (m, 2H).

Example 3

Intermediate 5c (R²═Cl): ¹H NMR (400 MHz, DMSO) δ 8.61 (s, 1H), 7.81 (d, J=7.6 Hz, 1H), 4.23 (m, 3H), 1.28 (t, J=7.1 Hz, 311), 1.21-10.08 (dd, J=7.1, 2.2 Hz, 2H), 0.99-0.92 (m, 2H).

Example 4

Intermediate 5d: ¹H NMR (400 MHz, CDCl₃) δ 8.59-8.51 (d, J=3.1 Hz, 1H), 8.03-7.92 (d, J=7.5 Hz, 1H), 4.98-4.73 (dddd, J=62.9, 6.3, 4.9, 3.4 Hz, 18), 4.44-4.34 (q, J=7.1 Hz, 2H), 3.91-3.83 (dt, J=8.6, 5.4 Hz, 1H), 2.95-2.88 (s, 3H), 1.59-1.48 (m, 1H), 1.45-1.38 (t, J=7.1 Hz, 3H), 1.35-1.18 (m, 1H).

Example 5

Intermediate 5e: ¹H NMR (400 MHz, CDCl₃) δ 8.51-8.43 (d, J=2.0 Hz, 1H), 7.94-7.86 (d, J=7.6 Hz, 1H), 4.90-4.65 (dddd, J=62.7, 6.0, 5.1, 3.3 Hz, 1H), 4.37-4.28 (q, J=7.1 Hz, 2H), 3.80-3.76 (s, 3H), 3.75-3.69 (dt, J=8.7, 5.5 Hz, 1H), 1.61-1.47 (m, 2H), 1.46-1.30 (m, 4H).

Example 6

Intermediate 5f: ¹H NMR (400 MHz, DMSO) δ 8.65 (s, 1H), 7.48 (d, J=8.16 Hz, 1H), 4.79 (q, J=6.65 Hz, 1H), 4.62 (dd, J=1.82, 11.36 Hz, 1H), 4.44 (dd, J 2.20, 11.36 Hz, 18), 4.23 (qd, J=2.95, 7.09 Hz, 2H), 1.40 (d, J=6.65 Hz, 3H), 1.28 (t, J=7.09 Hz, 3H).

General Scheme II outlined the preparation of required boronic acids and boronates. They are readily prepared through general methods.

Example 7 Synthesis of Boronic Acid 7

Reaction reagents and conditions: a. 1) NaH, THF, r.t.; 2) nBuLi, B(OiPr)₃. −70° C. to 0° C. 7.1 Boronic acid 7: To a solution of compound 6 (10 g, 44.44 mmol) in dry tetrahydrofuran (350 mL) was added sodium hydride (2 g, 66.66 mmol, 80% dispersion) at 0° C. After the mixture was stirred at room temperature for 30 min, the mixture was cooled below −60° C. in a dry ice/acetone bath, and n-butyllithium (70 mL, 112 mmol, 1.6 M in hexane) was added over 30 min. The mixture was kept stirring for another 30 min, then triisopropyl borate (40 mL, 177 mmol) was added dropwise. The reaction mixture was stirred for 10 min, and then warmed to 0° C. slowly in an ice bath. HCl (5 N) was added to the mixture to adjust pH=3-4, and the mixture was stirred for 20 min. Aq. NaOH was added to the mixture to adjust pH=10. After filtration, the organic layer was separated. The aqueous layer was extracted with a mixture of ethyl acetate/THF (4/1; 2×120 mL) and EtOAc (100 mL). The aqueous layer was adjusted to pH=5-6 with HCl. The precipitate thus formed was collected by filtration and dried to give boronic acid 7 (3.5 g, 41%) as a white solid.

Example 8 Synthesis of Boronate 10

8.1 Compound 9: 2-Aminonicotinonitrile 8 (100 g, 0.839 mol) was dissolved in HOAc (800 mL). To the solution was added Na₂CO₃ (88.97 g, 0.839 mol). Then, Br₂ (46.4 mL, 0.923 mal) was added dropwise. The reaction mixture was stirred at room temperature for 50 min. To the mixture was added water (600 mL). The mixture was cooled to about 5° C. The precipitate thus formed was collected by filtration and dried to give compound 9 (207 g, 96%). 8.2 Boronate 10: Compound 9 (50 g, 0.224 mol), bis(pinacolato)diboron (85.6 g, 0.337 mol), KOAc (44.1 g, 0.449 mol) and Pd(dppf)Cl₂.CH₂Cl₂ (2.77 g, 3.4 mmol) were charged into a flask. Dioxane (400 mL) was added. The reaction mixture was stirred at 100° C. for 2 hr under Ar. When LC-MS indicated that the reaction was completed, the mixture was cooled to room temperature. The mixture was filtered through diatomite, concentrated, diluted with a mixture of ethyl acetate and hexane in 3/1 ratio (1000 mL), filtered through silica gel (300-400 mesh), concentrated, crystallized and dried to give boronate 10 (32 g, 66%) as a white solid.

Example 9 Synthesis of Boronate 13

9.1 Compound 12: 3-Chloropyridin-2-amine (100 g, 0.778 mol) was dissolved in acetic acid (1200 mL). To the solution was added Na₂CO₃ (82.4 g, 0.778 mol). Then, Br₂ (39.1 mL, 0.856 mmol) was added dropwise. After addition, the reaction mixture was stirred at room temperature for 30 min. To the mixture was added water (800 mL). The mixture was cooled to about 5° C. The resulting solid was collected by filtration and dried to give compound 12 (147 g, 91%) as a white solid. 9.2 Boronate 13: Compound 12 (4 g, 17.2 mmol), bis(pinacolato)diboron (4.79 g, 18.8 mmol), KOAc (3.37 g, 34.2 mmol) and Pd(dppf)Cl₂.CH₂Cl₂ (0.210 g, 0.25 mmol) were charged into a flask. Dioxane (80 mL) was added. The mixture was stirred at 85° C. for 2 hr under Ar. When LC-MS indicated that the reaction was completed, the mixture was cooled to room temperature. The mixture was filtered through diatomite and concentrated. The residue was diluted with ethyl acetate and hexane (3/1, 100 mL), filtered through silica gel (300-400 mesh), concentrated and crystallized by n-hexane to give boronate 13 (3.4 g, 78%) as a white solid.

Example 10 Synthesis of Compound 1-2

10.1 Compound 16: Intermediate 5a (30 g, 65=-ol), boronic acid 7 (17 g, 71.6 mmol) and K₂CO₃ (27, 195 mmol) were charged into a flask. Dioxane (600 mL) and water (60 mL) were added. The solution was deoxygenated with N_(Y) for 15 min. Pd(dppf)Cl₂.CH₂Cl₂ (2.8 g, 3.24 mmol) was added to the mixture. The reaction mixture was stirred at 85° C. overnight. When the reaction was completed, the reaction mixture was cooled to room temperature. The precipitate was filtered, dissolved in water, filtered, triturated with EtOH, filtered and dried to give compound 16 (16 g, 57%) as an off-white solid. The obtained compound was pure enough for use.

The organic filtrate was concentrated. To the residue were added water, dichloromethane and EtOAc. The precipitate thus formed was collected by filtration and dissolved in HCl (5 N). After filtration to remove Pd residue, the filtrate was basified with aq. NaOH (pH=7-8). The precipitate was collected by filtration and dried to give compound 16 (3 g, 11%) as an off-white solid.

10.2 Compound 1-2: Compound 16 (33 g, 76.1 mmol) was suspended in EtOH (300 mL). Aq. NaOH (4 N, 100 mL) was added to the suspension, and the mixture was stirred at 60° C. for 2 hr. 200 mL of EtOH was evaporated under reduced pressure. To the residue was added HCl (5 N) to adjust pH=4. The resulting precipitate was filtered, triturated with EtOH, filtered and dried to give compound 1-2 (30 g, 97%) as an off-white solid. m.p.>300° C. ¹H NMR (400 MHz, DMSO) δ 14.64 (s, 1H), 12.39 (s, 1H), 8.92 (s, 1H), 8.58 (s, 1H), 8.28 (s, 1H), 8.01 (m, 2H), 6.67 (d, J=9.4 Hz, 1H), 4.42 (s, 1H), 2.68 (s, 3H), 1.27 (d, J=6.4 Hz, 2H), 1.12-1.03 (m, 2H). ¹³C NMR (101 MHz, DMSO) δ 176.92, 165.25, 162.85, 158.16, 155.72, 152.71, 150.92, 149.62, 139.29, 138.79, 137.62, 133.70, 133.52, 131.80, 127.47, 127.38, 123.75, 123.42, 113.89, 108.05, 107.81, 107.29, 41.29, 20.64, 20.62, 10.62. HPLC-MS m/z 406 (MH⁺). Anal. Calcd for C₂₂H₁₆FN₃O₄: C, 65.18, H, 3.98, N, 10.37. Found: C, 63.50, H, 4.00, N, 9.91.

Example 11 Synthesis of Compound 2-18

11.1 Compound 17: Boronate 10 (14 g, 56.1 mmol), intermediate 5a (20 g, 46.7 mmol), Cs₂CO₃ (15.22 g, 46.7 mmol.) and Pd(dppf)Cl₂.CH₂Cl₂ (0.98 g, 1.2 mmol) were charged into a flask. Dioxane (500 mL) and water (5 mL) were added. The mixture was stirred at 110° C. overnight under Ar. The mixture was cooled to room temperature. The mixture was filtered, and the solid was washed with dioxane and ethyl acetate. The solid was dissolved in hot CH₂Cl₂ (1200 mL), and the solution was filtered through diatomite. The operation was repeated twice. The organic layers were combined and concentrated. To the residue was added ethyl acetate (200 mL). The solid was collected by filtration, washed with ethyl acetate (60 mL) and dried to give compound 17 (17.6 g, 90%) as a white solid.

11.2 Compound 2-18: Compound 17 (43 g, 0.101 mol) was dissolved in THE and EtOH (1/1, 500 mL). To the solution was added NaOH (60 mL, 4 N). The mixture was stirred at room temperature for 2 hr. HCl (63 mL, 4 N) was added to acidify the mixture (pH=3-4). The solid was collected by filtration, washed with EtOH (100 mL) and dried to give compound 2-18 (35.7 g, 99%) as a white solid. m.p.>300° C. ¹H NMR (400 MHz, DMSO) δ 14.65 (s, 1H), 8.89 (s, 1H), 8.32-8.23 (m, 1H), 8.08 (d, J=2.09 Hz, 11H), 7.94 (d, J=8.87 Hz, 1H), 7.28 (s, 2H), 4.40 (tt, J=3.74, 7.17 Hz, 1H), 2.67 (s, 3H), 1.31-1.19 (m, 2H), 1.10-0.99 (m, 2H). ¹³C NMR (101 MHz, DMSO) δ 176.95, 176.92, 165.32, 159.60, 158.29, 155.86, 154.07, 152.67, 143.59, 139.32, 133.39, 133.22, 131.73, 127.13, 127.05, 116.93, 116.52, 107.96, 107.71, 107.27, 89.15, 41.32, 20.64, 20.62, 10.65. HPLC-MS m/z 379 (MH⁺). Anal. Calcd for C₂₀H₁₅FN₄O₃: C, 63.49, H, 4.00, N, 14.81. Found: C, 62.04, H, 4.20, N, 13.97.

Example 12 Synthesis of Compound 3-11

12.1 Compound 18: Boronate 13 (20 g, 75.4 mmol), intermediate 5a (24.1 g, 58.03 mmol), Cs₂CO₃ (26.5 g, 81.2 mmol) and Pd(dppf)Cl₂.CH₂Cl₂ (1.42 g, 1.7 mmol) were charged into a flask. Dioxane (400 mL) and water (4 mL) were added. The mixture was stirred at 100° C. overnight under Ar. The mixture was cooled to room temperature. The mixture was filtered, and the solid was washed with dioxane and ethyl acetate. The solid was dissolved in hot CH₂Cl₂ (1200 mL), and the solution was filtered through diatomite. The operation was repeated twice. The organic layers were combined and concentrated. To the residue was added ethyl acetate (200 mL). The solid was collected by filtration, washed with ethyl acetate (60 mL) and dried to give compound 18 (21 g, 85%) as a white solid. 12.2 Compound 19: Compound 18 (39 g, 91.91 mmol) was dissolved in THE and EtCH (1/1, 600 mL). To the mixture was added NaOH (4 N, 60 mL). The mixture was stirred at room temperature for 2 hr. HCl (4 N, 62 mL) was added to acidify the solution (pH=3-4). The solid was collected by filtration, washed with EtCH (100 mL) and dried to give compound 19 (34 g, 98%) as a white solid. 12.3 Compound 3-11: Chloroacetaldehyde (40% in water, 80 mL) was added to a solution of compound 19 (34 g, 91.9 mmol) in EtOH (600 ml). The mixture was refluxed for 3 hr. When LC-MS indicated that the reaction was completed, the mixture was cooled to 5° C. and filtered. The solid was dried to give compound 3-11 (21 g). The mother liquid was basified (pH=7-8) with aq. NaOH. The precipitate was collected by filtration, washed with EtOH and dried to give compound 3-1.1 (11.5 g) as a white solid. In total, 32.5 g of compound 3-11 was obtained in 93% yield. m.p.: 307-311° C. ¹H NMR (400 MHz, DMSO) δ 14.53 (s, 1H), 8.98-8.84 (m, 2H), 8.28 (d, J=1.16 Hz, 1H), 7.98 (d, J=8.83 Hz, 1H), 7.90 (d, J=0.89 Hz, 1H), 7.77 (s, 1H), 4.43 (tt, J=3.70, 7.10 Hz, 1H), 3.50-3.36 (m, 1H), 2.72 (s, 3H), 1.26 (d, J=6.80 I-z, 2H), 1.07 (d, J=18.24 Hz, 2H). ¹³C NMR (101 MHz, DMSO) δ 176.91, 176.88, 165.23, 158.22, 155.77, 152.84, 139.98, 139.17, 139.16, 132.44, 132.15, 131.98, 131.54, 127.86, 127.78, 127.38, 120.72, 118.97, 116.37, 108.15, 107.91, 107.37, 41.38, 20.54, 20.52, 10.72. HPLC-MS: m/z 412 (MH⁺). Anal. Calcd for C₂₁H₁₅ClFN₃O₃: C, 61.25, H, 3.67, N, 10.20. Found: C, 58.59, H, 3.86, N, 9.76.

Compounds listed in the following Tables were synthesized according to General Scheme III.

TABLE 1

Com- pound MS No. R³ = R² = R¹ = NMR (MH⁺) HPLC 1-1

OMe Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.63 (s, 1H), 12.41 (s, 1H), 8.82 (s, 1H), 8.69 (s, 1H), 8.38 (s, 1H), 8.05 (d, J = 9.6 Hz, 1H), 7.99 (d, J = 9.1 Hz, 1H), 6.66 (dd, J = 9.5, 1.6 Hz, 1H), 4.24 (s, 1H), 3.42 (s, 3H), 1.19 (d, J = 7.2 Hz, 4H). 422 98% 1-2

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.64 (s, 1H), 12.39 (s, 1H), 8.92 (s, 1H), 8.58 (s, 1H), 8.28 (s, 1H), 8.01 (m, 2H), 6.67 (d, J = 9.4 Hz, 1H), 4.42 (s, 1H), 2.68 (s, 3H), 1.27 (d, J = 6.4 Hz, 2H), 1.12-1.03 (m, 2H). 406 98% 1-3

OMe

¹H NMR (400 MHz, DMSO) δ 14.49 (s, 1H), 12.41 (s, 1H), 8.85 (d, J = 1.3 Hz, 1H), 8.67 (s, 1H), 8.36 (s, 1H), 8.05 (d, J = 9.6 Hz, 1H), 8.00 (d, J = 9.1 Hz, 1H), 6.77-6.54 (m, 1H), 5.24-4.97 (m, 1H), 4.29-4.10 (m, 1H), 3.44 (s, 3H), 1.89- 1.59 (m, 2H). 440 98% 1-4

Me

¹H NMR (400 MHz, DMSO) δ 14.50 (s, 1H), 12.39 (s, 1H), 8.90 (d, J = 3.0 Hz, 1H), 8.58 (s, 1H), 8.27 (s, 1H), 8.02 (m, 2H), 6.74-6.61 (m, 1H), 5.17 (dd, J = 64.3, 3.1 Hz, 1H), 4.39 (m, 1H), 2.60 (s, 3H), 1.84- 1.50 (m, 2H). 424 98% 1-5

Cl Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.22 (s, 1H), 12.42 (s, 1H), 8.94 (s, 1H), 8.61 (d, J = 2.0 Hz, 1H), 8.31 (d, J = 2.0 Hz, 1H), 8.20 (d, J = 8.5 Hz, 1H), 8.03 (d, J = 9.6 Hz, 1H), 6.67 (d, J = 9.5 Hz, 1H), 4.51- 4.34 (m, 1H), 1.29-1.19 (m, 2H), 1.17-1.05 (m, 2H). 426 98% 1-7

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.65 (s, 1H), 11.27 (s, 1H), 8.91 (s, 1H), 8.04 (d, J = 9.5 Hz, 1H), 7.98 (d, J = 8.8 Hz, 1H), 7.78 (s, 2H), 6.69 (d, J = 9.5 Hz, 1H), 4.49-4.30 (m, 1H), 2.65 (s, 3H), 1.25 (d, J = 6.7 Hz, 2H), 1.08 (s, 2H). 439 98% 1-8

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.66 (s, 1H), 11.99 (s, 1H), 8.91 (s, 1H), 8.03 (d, J = 9.1 Hz, 1H), 7.98 (d, J = 8.8 Hz, 1H), 7.60 (s, 1H), 7.57 (d, J = 11.5 Hz, 1H), 6.66 (d, J = 9.6 Hz, 1H), 4.51-4.29 (m, 1H), 1.25 (d, J = 6.3 Hz, 2H), 1.15-0.94 (m, 2H). 423 98% 1-9

OMe Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.64 (s, 1H), 11.30 (s, 1H), 8.82 (s, 1H), 8.15-8.03 (m, 1H), 8.00-7.93 (d, J = 9.1 Hz, 1H), 7.93-7.80 (d, J = 12.9 Hz, 2H), 6.79-6.51 (d, J = 9.4 Hz, 1H), 4.28-4.15 (m, 1H), 3.51-3.38 (s, 3H), 1.31- 1.09 (m, 4H). 455 93% 1-10

OMe Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.69-14.59 (s, 1H), 12.08-11.94 (s, 1H), 8.90-8.74 (s, 1H), 8.13- 8.01 (d, J = 1.8 Hz, 1H), 7.99-7.91 (d, J = 9.1 Hz, 1H), 7.77-7.71 (s, 1H), 7.68-7.59 (d, J = 11.6 Hz, 1H), 6.71-6.62 (d, J = 9.6 Hz, 1H), 4.30-4.17 (ddd, J = 11.2, 7.5, 4.7 Hz, 1H), 3.47-3.39 (s, 3H), 1.22- 1.11 (m, 4H). 439 95% 1-11

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.68 (s, 1H), 9.92 (s, 1H), 8.91 (s, 1H), 8.09 (d, J = 9.6 Hz, 1H), 7.99 (d, J = 8.8 Hz, 1H), 7.81 (s, 1H), 7.62-7.53 (m, 4H), 7.52-7.47 (m, 1H), 7.46 (s, 1H), 6.65 (d, J = 9.5 Hz, 1H), 4.65-4.23 (m, 1H), 2.70 (s, 3H), 1.24 (d, J = 7.0 Hz, 2H), 1.07 (s, 2H). 481 98% 1-12

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.68 (s, 1H), 12.23 (s, 1H), 8.92 (s, 1H), 8.10 (d, J = 9.5 Hz, 1H), 8.00 (d, J = 8.7 Hz, 1H), 7.87 (s, 1H), 7.70 (s, 1H), 6.70 (d, J = 9.3 Hz, 1H), 4.43 (s, 1H), 2.64 (s, 3H), 1.23 (s, 2H), 1.07 (d, J = 12.5 Hz, 2H). 489 98% 1-13

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.66 (s, 1H), 10.55 (s, 1H), 8.91 (s, 1H), 8.04 (d, J = 9.5 Hz, 1H), 7.99 (d, J = 8.7 Hz, 1H), 7.84 (s, 1H), 7.74 (s, 1H), 6.68 (d, J = 9.4 Hz, 1H), 4.75 (s, 1H), 4.40 (m, 1H), 2.64 (s, 3H), 1.25 (d, J = 6.9 Hz, 2H), 1.08 (s, 2H). 429 90% 1-14

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.70 (s, 1H), 11.06 (s, 1H), 8.91 (s, 1H), 8.05-7.87 (m, 2H), 7.31 (s, 1H), 7.16 (s, 1H), 6.60 (d, J = 9.5 Hz, 1H), 4.40 (dd, J = 7.0, 3.4 Hz, 1H), 3.94 (s, 3H), 2.65 (s, 3H), 1.25 (d, J = 7.1 Hz, 2H), 1.08 (s, 2H). 435 90% 1-15

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.65 (s, 1H), 10.97 (s, 1H), 8.92 (s, 1H), 8.28-8.06 (m, 2H), 8.01 (d, J = 8.8 Hz, 1H), 7.95 (s, 1H), 6.74 (d, J = 8.5 Hz, 1H), 4.49-4.33 (m, 1H), 2.64 (s, 3H), 1.25 (d, J = 6.8 Hz, 2H), 1.10 (s, 2H). 473 90% 1-16

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.72 (s, 1H), 11.95 (s, 1H), 8.91 (s, 1H), 7.99 (d, J = 7.9 Hz, 2H), 7.76 (s, 1H), 7.54 (d, J = 8.4 Hz, 1H), 7.47 (d, J = 8.4 Hz, 1H), 6.59 (d, J = 9.5 Hz, 1H), 4.40 (s, 1H), 2.63 (s, 3H), 1.25 (d, J = 6.1 Hz, 2H), 1.07 (s, 2H). 405 98% 1-17

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.66 (s, 1H), 10.76 (s, 1H), 8.92 (s, 1H), 8.03 (d, J = 9.7 Hz, 1H), 7.99 (d, J = 8.8 Hz, 1H), 7.93 (s, 1H), 7.83 (s, 1H), 6.68 (d, J = 9.4 Hz, 1H), 2.65 (s, 3H), 1.25 (m, 2H), 1.07 (m, 2H). 482; 484 96% 1-18

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.63 (s, 1H), 11.86 (s, 1H), 8.92 (s, 1H), 8.16 (m, 3H), 8.00 (d, J = 8.7 Hz, 1H), 6.80 (s, 1H), 4.42 (s, 1H), 2.65 (s, 3H), 1.26 (m, 2H), 1.09 (m, 2H). 430 96% 1-19

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.69 (s, 1H), 11.10 (s, 1H), 8.90 (s, 1H), 7.97 (t, J = 9.04 Hz, 2H), 7.58 (s, 1H), 7.39 (s, 1H), 6.59 (d, J = 9.48 Hz, 1H), 4.39 (dt, J = 3.29, 6.75 Hz, 1H), 3.36 (s, 3H), 2.63 (s, 3H), 1.25 (d, J = 6.45 Hz, 2H), 1.06 (s, 2H). 419 96% 1-20

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.64 (s, 1H), 8.93 (s, 1H), 8.21 (s, 1H), 8.18 (s, 1H), 8.15 (d, J = 9.7 Hz, 1H), 8.02 (d, J = 8.9 Hz, 1H), 6.81 (d, J = 9.7 Hz, 1H), 6.24 (s, 2H), 4.41 (m, 2H), 2.65 (s, 4H), 1.25 (m, 2H), 1.10 (m, 2H). 461 90% 1-21

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.75 (s, 1H), 12.18 (s, 1H), 8.91 (s 1H), 8.14 (s, 1H), 7.96 (d, J = 8.8 Hz, 1H), 7.78 (d, J = 7.7 Hz, 1H), 7.60 (d, J = 7.8 Hz, 1H), 7.41 (d, J = 7.9 Hz, 1H), 7.28 (d, J = 7.4 Hz, 1H), 4.43 (s, 1H), 2.71 (s, 3H), 1.24 (s, 2H), 1.05 (s, 2H). 405 98% 1-22

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.75 (s, 1H), 8.91 (s, 1H), 8.16 (s, 1H), 7.96 (d, J = 8.2 Hz, 1H), 7.90 (s, 1H), 7.85 (d, J = 7.3 Hz, 1H), 7.66 (d, J = 8.5 Hz, 1H), 7.38 (d, J = 6.7 Hz, 1H), 4.42 (s, 1H), 3.74 (s, 3H), 2.69 (s, 3H), 1.23 (s, 2H), 1.05 (s, 2H). 419 95% 1-23

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.72 (s, 1H), 12.04 (s, 1H), 8.93 (s, 1H), 8.04 (d, J = 8.2 Hz, 1H), 7.68 (t, J = 7.5 Hz, 1H), 7.48 (d, J = 8.1 Hz, 1H), 7.35 (d, J = 9.7 Hz, 1H), 7.17 (d, J = 7.1 Hz, 1H), 6.49 (d, J = 9.7 Hz, 1H), 4.39 (s, 1H), 2.50 (s, 3H), 1.16 (m, 4H). 405 96% 1-24

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.82 (s, 1H), 10.88 (s, 1H), 8.95 (s, 1H), 8.20-7.94 (m, 2H), 7.86 (d, J = 30.6 Hz, 1H), 7.44 (d, J = 7.5 Hz, 1H), 7.36 (s, 1H), 6.57 (s, 1H), 4.41 (s, 1H), 2.67 (s, 3H), 1.47-0.92 (m, 4H). 405 90% 1-25

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.66 (s, 1H), 12.12 (s, 1H), 8.94 (s, 1H), 8.06 (d, J = 8.5 Hz, 1H), 7.58 (s, 1H), 7.45 (d, J = 7.0 Hz, 1H), 7.13 (s, 1H), 7.02 (d, J = 8.0 Hz, 1H), 6.65 (s, 1H), 4.40 (m, 1H), 2.62 (s, 3H), 1.28-1.04 (m, 4H). 405 90% 1-26

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.70 (s, 1H), 11.88 (s, 1H), 8.92 (s, 1H), 8.01 (d, J = 8.8 Hz, 2H), 7.86 (d, J = 7.8 Hz, 1H), 7.29 (s, 1H), 7.22 (d, J = 7.6 Hz, 1H), 6.60 (d, J = 9.6 Hz, 1H), 4.40 (s, 1H), 2.62 (s, 3H), 1.24 (d, J = 5.6 Hz, 2H), 1.07 (s, 2H). 405 94% 1-27

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.80 (s, 1H), 11.57 (s, 1H), 11.48 (s, 1H), 8.97 (s, 1H), 8.04 (d, J = 8.5 Hz, 1H), 7.82 (s, 1H), 7.60 (d, J = 8.1 Hz, 1H), 7.49 (d, J = 8.2 Hz, 1H), 5.86 (s, 1H), 4.45 (s, 1H), 2.68 (s, 3H), 1.30 (d, J = 5.7 Hz, 2H), 1.13 (s, 2H). 421 98% 1-28

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.75 (s, 1H), 10.73 (s, 1H), 8.90 (s, 1H), 7.97 (d, J = 8.4 Hz, 1H), 7.89 (s, 1H), 7.43 (s, 1H), 7.28 (d, J = 7.6 Hz, 1H), 4.40 (s, 1H), 2.62 (s, 3H), 1.24 (s, 2H), 1.06 (s, 2H). 466 96% 1-29

OMe Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.69 (s, 1H), 11.96 (s, 1H), 8.81 (s, 1H), 8.01 (d, J = 9.6 Hz, 1H), 7.95 (d, J = 9.1 Hz, 1H), 7.87 (s, 1H), 7.68 (d, J = 8.6 Hz, 1H), 7.49 (d, J = 8.6 Hz, 1H), 6.57 (dd, J = 9.5, 1.7 Hz, 1H), 4.32-4.10 (m, 1H), 3.38 (s, 3H), 1.18 (m, 4H). 421 98% 1-30

Cl Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.41 (s, 1H), 11.96 (s, 1H), 8.91 (s, 1H), 8.20 (d, J = 8.8 Hz, 1H), 7.95 (d, J = 9.1 Hz, 1H), 7.80 (s, 1H), 7.68 (d, J = 8.6 Hz, 1H), 7.49 (d, J = 8.6 Hz, 1H), 6.62 (dd, J = 9.5, 1.7 Hz, 1H), 4.32-4.10 (m, 1H), 1.30 (m, 2H), 1.18 (m, 2H). 425 96% 1-31

OMe Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.67 (s, 1H), 11.89 (s, 1H), 8.82 (s, 1H), 8.17-7.90 (m, 2H), 7.85 (d, J = 8.0 Hz, 1H), 7.48 (s, 1H), 7.35 (d, J = 7.9 Hz, 1H), 6.60 (d, J = 11.2 Hz, 1H), 4.28-4.14 (m, 1H), 3.41 (s, 4H), 1.18 (m, 4H). 421 90% 1-32

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.69 (s, 1H), 11.78 (s, 1H), 8.91 (s, 1H), 7.98 (d, J = 8.77 Hz, 1H), 7.72 (s, 1H), 7.54 (s, 1H), 7.50-7.44 (m, 1H), 6.48 (s, 1H), 2.63 (s, 3H), 2.44 (s, 3H), 1.28-1.21 (m, 2H), 1.12- 1.02 (m, 2H). 419 96% 1-33

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.62 (s, 1H), 13.15 (s, 1H), 8.92 (s, 1H), 8.87 (s, 1H), 8.77 (d, J = 1.74 Hz, 1H), 8.38 (d, J = 1.97 Hz, 1H), 8.02 (d, J = 8.86 Hz, 1H), 4.42 (tt, J = 3.74, 7.15 Hz, 1H), 2.66 (s, 3H), 1.25 (q, J = 6.85 Hz, 2H), 1.08 (s, 2H). 431 96% 1-34

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 9.11 (s, 1H), 8.92 (s, 1H), 8.31 (d, J = 8.86 Hz, 1H), 8.16 (d, J = 8.54 Hz, 1H), 8.03 (d, J = 8.91 Hz, 1H), 6.51 (s, 1H), 4.44 (tt, J = 3.64, 7.02 Hz, 2H), 2.69 (s, 3H), 2.51 (s, 3H), 1.24 (d, J = 6.83 Hz, 2H), 1.10 (s, 2H). 420 95% 1-35

OMe Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.75-14.55 (m, 1H), 9.83-9.67 (d, J = 3.2 Hz, 1H), 8.89-8.73 (s, 1H), 7.96- 7.86 (d, J = 9.1 Hz, 1H), 7.58-7.47 (s, 1H), 7.42- 7.34 (s, 1H), 4.30-4.14 (tt, J = 7.3, 4.5 Hz, 1H), 3.52- 3.39 (s, 3H), 3.11-2.95 (t, J = 7.5 Hz, 2H), 2.62-2.56 (dd, J = 8.5, 6.3 Hz, 2H), 1.21-1.12 (m, 4H). 457 99% 1-36

OMe Cyclopropyl ¹H NMR (400 MHz, CDCl₃) δ 14.52-14.39 (s, 1H), 8.87-8.82 (s, 1H), 8.01-7.92 (m, 1H), 7.75-7.69 (s, 1H), 7.39-7.34 (t, J = 1.7 Hz, 1H), 7.21-7.18 (s, 1H), 6.79-6.69 (dd, J = 17.3, 11.0 Hz, 1H), 5.70-5.62 (d, J = 17.3 Hz, 1H), 5.54-5.44 (d, J = 11.0 Hz, 1H), 4.09-3.99 (d, J = 3.7 Hz, 1H), 3.45-3.36 (s, 3H), 3.03- 2.95 (dd, J = 8.5, 6.5 Hz, 2H), 2.68-2.59 (dd, J = 8.7, 6.5 Hz, 2H), 1.26-1.21 (dd, J = 5.2, 1.8 Hz, 2H), 1.11- 1.03 (dt, J = 4.0, 1.9 Hz, 2H). 449 85% 1-37

OMe Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.73-14.60 (s, 1H), 10.38-10.26 (s, 1H), 8.84-8.76 (s, 1H), 7.96-7.88 (d, J = 9.1 Hz, 1H), 7.36-7.28 (d, J = 11.2 Hz, 1H), 7.25- 7.19 (s, 1H), 4.29-4.18 (ddd, J = 11.3, 7.3, 4.4 Hz, 1H), 3.47-3.43 (s, 3H), 3.07-2.99 (t, J = 7.4 Hz, 2H), 2.60-2.53 (dd, J = 8.5, 6.5 Hz, 2H), 1.21-1.08 (d, J = 5.3 Hz, 4H). 441 85% 1-38

OMe Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.70 (s, 1H), 9.62 (s, 1H), 8.79 (s, 1H), 7.89 (d, J = 9.2 Hz, 1H), 7.20 (d, J = 8.5 Hz, 2H), 4.39-4.16 (m, 1H), 3.42 (s, 3H), 3.03-2.88 (m, 2H), 2.54 (m, 5H), 1.16 (m, 4H). 436 99% 1-39

OMe Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 15.13-14.27 (m, 1H), 10.76-10.64 (s, 5H), 8.98-8.88 (s, 1H), 8.19- 8.14 (d, J = 2.2 Hz, 1H), 8.00-7.94 (d, J = 8.7 Hz, 1H), 7.75-7.70 (d, J = 2.1 Hz, 1H), 4.49-4.32 (tt, J = 7.3, 3.8 Hz, 1H), 3.03-2.95 (m, 2H), 2.69-2.64 (s, 3H), 2.62-2.56 (t, J = 7.5 Hz, 2H), 1.28-1.22 (m, 2H), 1.09-1.03 (m, 2H). 408 90% 1-40

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.60 (s, 1H), 12.01 (s, 1H), 8.92 (s, 1H), 8.53 (s, 1H), 8.08- 7.98 (m, 2H), 7.72 (s, 1H), 6.85 (d, J = 9.75 Hz, 1H), 4.41 (s, 1H), 3.34 (s, 1H), 2.65 (s, 3H), 2.54 (s, 3H), 1.24 (d, J = 6.54 Hz, 2H), 1.09 (s, 2H). 406 96% 1-41

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.85-14.51 (s, 1H), 9.00-8.91 (m, 2H), 8.60-8.53 (s, 1H), 8.18- 8.09 (t, J = 8.4 Hz, 2H), 8.09-8.02 (m, 1H), 7.95- 7.84 (s, 1H), 7.79-7.68 (s, 1H), 4.51-4.31 (s, 1H), 2.79-2.61 (s, 3H), 1.36-1.20 (d, J = 6.9 Hz, 2H), 1.16-1.04 (s, 2H). 389 100%  1-42

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 15.01-14.88 (d, J = 2.6 Hz, 1H), 8.95-8.82 (d, J = 2.5 Hz, 1H), 8.05-7.94 (d, J = 6.7 Hz, 1H), 7.89-7.77 (d, J = 9.4 Hz, 1H), 7.62-7.40 (m, 3H), 6.33-6.21 (s, 1H), 5.59-5.49 (s, 2H), 4.48-4.35 (s, 1H), 2.86-2.76 (s, 3H), 1.30-1.15 (d, J = 7.0 Hz, 2H), 1.00-0.88 (s, 2H). 392 100%  1-43

Me Cyclopropyl ¹H NMR (400 MHz, MeOD) δ 9.05-8.91 (s, 1H), 8.87-8.77 (s, 1H), 8.43-8.36 (s, 1H), 8.14-8.06 (d, J = 7.3 Hz, 1H), 8.02-7.88 (d, J = 21.7 Hz, 2H), 7.74-7.62 (d, J = 8.7 Hz, 1H), 7.59-7.51 (s, 1H), 4.35-4.15 (s, 1H), 2.73-2.53 (m, 3H), 1.05-0.93 (s, 2H), 0.85-0.71 (d, J = 8.0 Hz, 2H). 389 97% 1-44

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.72-14.59 (s, 1H), 9.01-8.91 (s, 1H), 8.88-8.80 (s, 1H), 8.66-8.56 (d, J = 8.6 Hz, 1H), 8.25-8.16 (d, J = 8.0 Hz, 1H), 8.14- 8.09 (s, 1H), 8.08-8.01 (d, J = 8.6 Hz, 1H), 7.95- 7.89 (d, J = 8.7 Hz, 1H), 7.88-7.79 (d, J = 7.7 Hz, 1H), 4.51-4.35 (s, 1H), 2.75-2.67 (s, 3H), 1.30-1.19 (d, J = 6.8 Hz, 2H), 1.16-1.07 (s, 2H). 405 97.5%   1-45

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.85-14.58 (s, 1H), 9.00-8.88 (s, 1H), 8.19-8.07 (d, J = 8.3 Hz, 1H), 8.07-7.94 (m, 4H), 7.68-7.58 (d, J = 6.0 Hz, 2H), 7.57-7.48 (d, J = 8.2 Hz, 1H), 4.49-4.33 (s, 1H), 2.72-2.59 (s, 3H), 1.33-1.19 (d, J = 7.4 Hz, 2H), 1.16-1.00 (s, 2H). 388 98% 1-46

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 9.69-9.59 (s, 1H), 9.01-8.92 (d, J = 2.5 Hz, 1H), 8.69-8.58 (d, J = 2.4 Hz, 1H), 8.47-8.34 (d, J = 7.6 Hz, 1H), 8.14- 8.04 (d, J = 8.1 Hz, 1H), 7.95-7.80 (t, J = 8.7 Hz, 2H), 7.57-7.46 (d, J = 7.9 Hz, 1H), 4.48- 4.34 (s, 1H), 2.52-2.50 (s, 3H), 1.29-1.01 (m, 4H). 389 98% 1-47

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.96-14.46 (s, 1H), 12.04-11.50 (s, 1H), 8.98-8.89 (s, 1H), 8.34-8.17 (d, J = 12.3 Hz, 1H), 8.17-8.01 (m, 2H), 7.97-7.90 (d, J = 8.1 Hz, 1H), 4.48-4.36 (dd, J = 7.3, 4.1 Hz, 1H), 2.66-2.56 (s, 3H), 1.31-1.17 (d, J = 7.1 Hz, 2H), 1.15-1.03 (s, 2H). 422 99% 1-48

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 9.19-9.11 (s, 1H), 8.98-8.92 (s, 1H), 8.45-8.39 (s, 1H), 8.13- 8.00 (dd, J = 16.7, 8.4 Hz, 2H), 7.80-7.69 (t, J = 7.7 Hz, 1H), 7.66-7.55 (t, J = 7.7 Hz, 1H), 7.38-7.29 (d, J = 8.3 Hz, 1H), 4.47-4.34 (s, 1H), 2.65-2.54 (s, 3H), 1.28-1.07 (m, 4H). 405 98% 1-49

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.69-14.45 (s, 1H), 10.31-10.19 (s, 1H), 9.06-8.94 (d, J = 3.6 Hz, 2H), 8.73-8.62 (d, J = 8.2 Hz, 1H), 8.61-8.43 (m, 2H), 8.32-8.21 (t, J = 7.5 Hz, 1H), 8.21-8.11 (m, 2H), 7.83-7.71 (d, J = 8.3 Hz, 1H), 4.67-4.52 (s, 3H), 4.50-4.39 (d, J = 7.6 Hz, 1H), 2.52-2.50 (m, 3H), 1.32- 1.03 (m, 4H). 404 100%  1-50

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.72-14.45 (s, 1H), 9.88-9.78 (s, 1H), 9.58-9.48 (s, 1H), 9.02-8.92 (s, 1H), 8.70-8.60 (d, J = 9.0 Hz, 1H), 8.59-8.51 (d, J = 8.2 Hz, 1H), 8.46-8.36 (t, J = 7.9 Hz, 1H), 8.24-8.06 (t, J = 9.7 Hz, 2H), 4.78-4.67 (s, 2H), 4.53-4.40 (s, 1H), 2.82-2.71 (s, 3H), 1.37-1.18 (d, J = 6.4 Hz, 2H), 1.16-1.07 (m, 2H). 404 98% 1-51

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 9.10-9.01 (d, J = 4.0 Hz, 1H), 8.98-8.91 (d, J = 2.6 Hz, 1H), 8.30-8.19 (d, J = 8.4 Hz, 1H), 8.14-8.07 (s, 1H), 8.05-7.97 (t, J = 7.7 Hz, 1H), 7.96-7.89 (d, J = 8.4 Hz, 1H), 7.78-7.68 (d, J = 6.8 Hz, 1H), 7.65-7.57 (m, 1H), 4.45-4.33 (s, 1H), 2.48- 2.40 (d, J = 2.8 Hz, 3H), 1.28-1.03 (m, 4H). 389 93.6%   1-52

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.78-14.66 (s, 1H), 9.06-8.97 (s, 1H), 8.96-8.88 (s, 1H), 8.54-8.46 (d, J = 8.1 Hz, 1H), 8.26-8.14 (d, J = 8.3 Hz, 1H), 8.14-8.06 (s, 1H), 8.06-7.98 (d, J = 8.6 Hz, 1H), 7.74-7.58 (d, J = 8.3 Hz, 2H), 4.51-4.29 (s, 1H), 2.73-2.60 (s, 3H), 1.29- 1.18 (d, J = 7.0 Hz, 2H), 1.15-1.07 (s, 2H). 389 100%  1-53

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 8.96-8.88 (d, J = 2.4 Hz, 1H), 8.85-8.78 (s, 1H), 8.57-8.47 (d, J = 8.2 Hz, 1H), 8.25-8.13 (d, J = 8.3 Hz, 1H), 8.03-7.95 (d, J = 8.3 Hz, 1H), 7.86-7.77 (m, 2H), 7.69-7.54 (d, J = 8.7 Hz, 1H), 4.44- 4.31 (s, 1H), 2.48-2.42 (s, 3H), 1.29-1.16 (d, J = 7.6 Hz, 2H), 1.15-1.02 (s, 2H). 389 98% 1-54

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 9.17-9.09 (s, 1H), 9.01-8.91 (d, J = 2.7 Hz, 1H), 8.26-8.17 (d, J = 8.5 Hz, 1H), 8.15-8.06 (d, J = 8.5 Hz, 1H), 7.94-7.84 (s, 1H), 2.48-2.42 (m, 2H), 7.72- 7.59 (d, J = 9.2 Hz, 2H), 7.56-7.45 (d, J = 8.3 Hz, 1H), 4.45-4.35 (s, 1H), 2.52-2.45 (s, 3H), 1.29-1.03 (dd, J = 16.6, 7.5 Hz, 4H). 389 98% 1-55

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 15.08-14.78 (s, 1H), 8.95-8.83 (s, 2H), 8.48-8.37 (d, J = 6.0 Hz, 1H), 8.33-8.19 (d, J = 8.2 Hz, 1H), 8.14-8.02 (d, J = 8.5 Hz, 1H), 7.94-7.76 (m, 2H), 7.68-7.59 (d, J = 7.1 Hz, 1H), 7.58-7.49 (t, J = 7.2 Hz, 1H), 4.47-4.34 (s, 1H), 2.73-2.56 (s, 3H), 1.31- 0.99 (m, 4H). 405 95% 1-56

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 9.00-8.91 (s, 1H), 8.85-8.75 (d, J = 6.1 Hz, 1H), 8.73-8.64 (d, J = 8.6 Hz, 1H), 8.13-8.05 (d, J = 8.4 Hz, 1H), 7.97-7.86 (d, J = 8.1 Hz, 1H), 7.80-7.71 (s, 1H), 7.65-7.58 (d, J = 5.8 Hz, 1H), 7.57- 7.48 (d, J = 8.4 Hz, 1H), 4.46-4.35 (s, 1H), 2.57-2.52 (s, 3H), 1.28-1.04 (m, 4H). 405 96% 1-57

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.95-14.35 (m, 1H), 9.01-8.90 (t, J = 2.0 Hz, 1H), 8.80- 8.63 (m, 2H), 8.13-8.06 (m, 1H), 8.04-7.95 (t, J = 7.8 Hz, 1H), 7.84-7.75 (d, J = 6.5 Hz, 1H), 7.52-7.41 (ddd, J = 10.0, 5.1, 2.5 Hz, 1H), 7.38-7.29 (d, J = 8.4 Hz, 1H), 4.46-4.32 (d, J = 6.9 Hz, 1H), 2.49-2.44 (s, 3H), 1.29- 0.99 (m, 4H). 405 93.3%   1-58

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 8.98-8.89 (s, 1H), 8.73-8.64 (d, J = 6.6 Hz, 1H), 8.58-8.52 (s, 1H), 8.35-8.26 (d, J = 8.2 Hz, 1H), 8.12- 7.99 (t, J = 10.7 Hz, 2H), 7.83-7.75 (d, J = 8.3 Hz, 1H), 7.65-7.53 (s, 1H), 4.46-4.36 (s, 1H), 2.65-2.59 (s, 3H), 1.29-1.19 (d, J = 7.8 Hz, 2H), 1.14-1.07 (s, 2H). 405 96.2%   1-59

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 8.96-8.87 (s, 1H), 8.75-8.64 (d, J = 7.2 Hz, 2H), 8.28-8.19 (s, 1H), 8.10-7.99 (d, J = 8.5 Hz, 2H), 7.90- 7.80 (d, J = 9.0 Hz, 1H), 7.63-7.52 (s, 1H), 4.48-4.34 (s, 1H), 2.65-2.57 (s, 3H), 1.30- 1.18 (d, J = 7.1 Hz, 2H), 1.14-1.02 (s, 2H). 405 99% 1-60

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 9.77-9.61 (s, 1H), 9.00-8.90 (d, J = 3.1 Hz, 1H), 8.75-8.62 (d, J = 5.8 Hz, 1H), 8.57-8.42 (d, J = 8.2 Hz, 1H), 8.31-8.21 (s, 1H), 8.22-8.13 (d, J = 5.3 Hz, 1H), 8.11-8.01 (d, J = 8.7 Hz, 1H), 7.94- 7.81 (d, J = 8.4 Hz, 1H), 4.49-4.34 (s, 1H), 389 93.6%   2.68-2.59 (s, 3H), 1.34-1.18 (d, J = 7.6 Hz, 2H), 1.15-1.00 (s, 2H). 1-61

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 9.19-9.10 (s, 1H), 9.03-8.95 (s, 1H), 8.37-8.27 (d, J = 6.9 Hz, 1H), 8.18-8.05 (m, 4H), 7.81-7.73 (d, J = 8.4 Hz, 1H), 4.52-4.42 (t, J = 5.2 Hz, 1H), 2.74-2.65 (s, 3H), 1.36-1.27 (d, J = 7.1 Hz, 2H), 1.19-1.10 (s, 2H). 405 1005  1-62

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.82-14.70 (s, 1H), 11.54-11.41 (s, 1H), 9.03-8.93 (s, 1H), 8.44-8.33 (d, J = 8.2 Hz, 1H), 8.14-8.01 (d, J = 8.0 Hz, 1H), 7.84-7.75 (s, 1H), 7.58-7.51 (d, J = 7.6 Hz, 1H), 7.39-7.26 (s, 1H), 6.76- 6.64 (d, J = 6.6 Hz, 1H), 4.52-4.40 (s, 1H), 2.70-2.61 (s, 3H), 1.37-1.22 (d, J = 6.8 Hz, 2H), 1.19-1.04 (s, 2H). 405 100%  1-63

¹H NMR (400 MHz, DMSO) δ 15.18 (s, 1H), 12.31 (s, 1H), 9.09 (s, 1H), 8.82 (d, J = 2.0 Hz, 1H), 8.45 (d, J = 1.7 Hz, 1H), 8.03 (t, J = 9.3 Hz, 2H), 7.76 (d, J = 8.4 Hz, 1H), 6.63 (d, J = 9.4 Hz, 1H), 5.00 (d, J = 6.7 Hz, 1H), 4.58 (d, J = 10.8 Hz, 1H), 4.45 (d, J = 10.0 Hz, 1H), 2.54 (s, 1H), 1.52 (d, J = 6.7 Hz, 3H). 390 98% 1-64

¹H NMR (400 MHz, DMSO) δ 14.96 (s, 1H), 12.35 (s, 1H), 9.10 (s, 1H), 8.68 (s, 1H), 8.34 (s, 1H), 8.01 (d, J = 9.53 Hz, 1H), 7.79 (d, J = 9.70 Hz, 1H), 6.64 (d, J = 9.45 Hz, 1H), 5.01 (d, J = 6.68 Hz, 1H), 4.60-4.54 (m, 1H), 4.46 (d, J = 9.78 Hz, 1H), 1.49 (d, J = 6.71 Hz, 3H). 408 96% 1-65

¹H NMR (400 MHz, DMSO) δ 9.27 (s, 1H), 8.95 (s, 1H), 8.87 (d, J = 15.4 Hz, 1H), 8.41-8.22 (m, 3H), 8.01 (t, J = 7.3 Hz, 1H), 7.85 (t, J = 7.3 Hz, 1H), 7.73 (d, J = 8.2 Hz, 1H), 4.45 (m, 1H), 2.77 (s, 3H), 1.31 (d, J = 6.2 Hz, 2H), 1.11 (s, 2H). 371 97%

TABLE 2

Com- pound MS No. R³ = R² = R¹ = NMR (MH⁺) HPLC 2-1

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 8.28 (s, 1H), 7.98 (s, 1H), 7.80 (s, 1H), 7.33 (d, J = 8.90 Hz, 1H), 7.16 (d, J = 9.30 Hz, 1H), 3.66 (d, J = 3.58 Hz, 1H), 1.96 (s, 3H), 0.58 (d, J = 5.78 Hz, 2H), 0.37 (d, J = 1.61 Hz, 2H). 357 94% 2-2

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 8.93 (s, 1H), 8.48 (d, J = 2.77 Hz, 1H), 8.13 (s, 1H), 8.01 (d, J = 8.72 Hz, 1H), 7.61 (s, 1H), 4.50-4.30 (m, 1H), 3.49 (d, J = 5.30 Hz, 5H), 3.36-3.29 (m, 5H), 2.66 (d, J = 15.95 Hz, 3H), 1.43 (s, 9H), 1.28-1.21 (m, 2H), 1.08 (s, 2H). 523 98% 2-3

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 8.92 (s, 1H), 8.79 (d, J = 5.61 Hz, 2H), 8.01 (d, J = 8.93 Hz, 1H), 7.50 (d, J = 5.50 Hz, 2H), 4.40 (s, 1H), 2.61 (s, 3H), 1.24 (d, J = 5.97 Hz, 2H), 1.07 (s, 2H). 339 98% 2-4

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 9.00 (s, 2H), 8.92 (s, 1H), 8.49 (d, J = 2.73 Hz, 1H), 8.12 (s, 1H), 7.98 (t, J = 11.57 Hz, 1H), 7.56 (s, 1H), 4.44-4.34 (m, 1H), 3.64 (s, 5H), 3.26 (s, 4H), 2.62 (s, 3H), 1.23 (d, J = 6.27 Hz, 2H), 1.07 (s, 2H). 423 95% 2-5

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 8.93 (s, 1H), 8.71 (t, J = 26.47 Hz, 1H), 8.04 (d, J = 8.68 Hz, 2H), 7.61 (d, J = 45.28 Hz, 1H), 4.44-4.38 (m, 1H), 2.55 (s, 2H), 2.34 (d, J = 9.33 Hz, 3H), 1.23 (s, 2H), 1.06 (dd, J = 4.45, 8.57 Hz, 2H). 353 95% 2-6

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.55 (s, 1H), 8.92 (s, 1H), 8.83 (t, J = 8.69 Hz, 1H), 8.65 (dt, J = 8.70, 17.42 Hz, 1H), 8.05 (d, J = 8.87 Hz, 1H), 7.73-7.52 (m, 1H), 4.41 (tt, J = 3.77, 7.16 Hz, 1H), 2.64 (s, 3H), 1.31-1.16 (m, 2H), 1.10-0.97 (m, 2H). 357 98% 2-7

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 8.93 (s, 1H), 8.85- 8.61 (m, 2H), 8.03 (d, J = 6.60 Hz, 1H), 7.96 (s, 2H), 7.69 (dd, J = 5.19, 7.64 Hz, 1H), 4.41 (ddd, J = 3.87, 7.26, 10.97 Hz, 2H), 2.75-2.72 (m, 5H), 1.33-1.20 (m, 3H), 1.13-1.03 (m, 2H). 339 98% 2-8

Me Cyclopropyl ¹H NMR (400, MHz, MeOD) δ 8.79 (s, 1H), 7.92- 7.71 (m, 2H), 7.55 (t, J = 17.62 Hz, 1H), 6.84 (t, J = 36.31 Hz, 1H), 4.16-4.04 (m, 1H), 3.02 (s, 5H), 1.09-1.01 (m, 2H), 0.81 (q, J = 7.23 Hz, 2H). 355 98% 2-9

Me Cyclopropyl ¹H NMR (400 MHz, MeOD) δ 8.06 (t, J = 38.62 Hz, 2H), 7.68 (dd, J = 8.35, 33.76 Hz, 2H), 7.47 (d, J = 8.87 Hz, 1H), 7.13-6.77 (m, 2H), 4.33 (s, 1H), 3.97 (d, J = 7.85 Hz, 3H), 2.20-1.90 (m, 2H), 1.35-1.22 (m, 1H), 1.05 (s, 1H). 369 98% 2-10

Me Cyclopropyl ¹H NMR (400 MHz, MeOD) δ 9.06 (s, 1H), 8.33 (s, 1H), 8.01 (d, J = 9.18 Hz, 1H), 7.67 (t, J = 24.14 Hz, 2H), 7.17 (s, 1H), 4.37 (s, 1H), 3.94 (s, 3H), 2.66 (s, 3H), 1.32 (d, J = 6.60 Hz, 2H), 1.07 (s, 2H). 369 98% 2-11

Me Cyclopropyl ¹H NMR (400 MHz, MeOD) δ 9.05 (s, 1H), 8.29 (s, 2H), 8.09 (d, J = 7.83 Hz, 1H), 7.94 (d, J = 23.80 Hz, 2H), 7.39-7.20 (m, 2H), 7.09 (s, 1H), 4.36 (s, 1H), 2.77 (s, 3H), 1.30 (s, 2H), 1.09 (s, 2H). 466 98% 2-12

Me Cyclopropyl ¹H NMR (400 MHz, MeOD) δ 9.02 (s, 1H), 8.40 (d, J = 92.33 Hz, 2H), 8.16-8.03 (m, 2H), 7.98-7.80 (m, 1H), 7.75-7.50 (m, 2H), 4.34 (s, 1H), 3.82 (d, J = 24.28 Hz, 4H), 3.45 (s, 4H), 2.70 (d, J = 23.16 Hz, 3H), 1.27 (dd, J = 11.61, 24.61 Hz, 3H), 1.09 (s, 2H). 424 98% 2-13

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.68 (s, 1H), 8.91 (s, 1H), 8.69 (s, 1H), 7.97 (d, J = 8.46 Hz, 1H), 7.79 (s, 1H), 7.63 (s, 1H), 4.40 (s, 1H), 3.82 (d, J = 6.95 Hz, 2H), 3.21 (s, 2H), 2.63 (d, J = 43.98 Hz, 3H), 1.22 (d, J = 5.36 Hz, 2H), 1.05 (s, 2H). 380 97% 2-14

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.69 (s, 2H), 8.91 (s, 1H), 8.49 (s, 2H), 8.24 (s, 2H), 7.98 (d, J = 8.62 Hz, 1H), 4.41 (s, 1H), 2.65 (d, J = 31.48 Hz, 3H), 1.24 (d, J = 6.48 Hz, 2H), 1.07 (s, 2H). 399 99% 2-15

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.67 (s, 1H), 8.91 (s, 1H), 8.13 (d, J = 25.11 Hz, 1H), 8.07 (s, 1H), 7.95 (dd, J = 8.95, 25.35 Hz, 2H), 7.06 (d, J = 8.71 Hz, 1H), 4.41 (s, 1H), 2.65 (d, J = 25.72 Hz, 3H), 1.22 (d, J = 5.45 Hz, 2H), 1.05 (s, 2H). 354 99% 2-16

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 8.91 (s, 1H), 8.74 (s, 1H), 8.54 (t, J = 24.30 Hz, 2H), 7.99 (d, J = 8.68 Hz, 1H), 4.41 (s, 1H), 3.10 (d, J = 17.91 Hz, 3H), 2.70 (s, 3H), 1.25 (d, J = 5.66 Hz, 2H), 1.07 (s, 2H). 413 99% 2-17

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.63 (s, 1H), 9.79 (s, 2H), 8.92 (s, 1H), 8.61 (s, 1H), 8.01 (d, J = 13.11 Hz, 2H), 4.67 (d, J = 32.94 Hz, 4H), 4.40 (s, 1H), 2.62 (s, 3H), 1.23 (s, 3H), 1.07 (s, 2H). 380 97% 2-18

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.65 (s, 1H), 8.89 (s, 1H), 8.27 (s, 1H), 8.07 (t, J = 6.62 Hz, 1H), 7.94 (d, J = 8.87 Hz, 1H), 7.28 (s, 2H), 4.40 (tt, J = 3.75, 7.16 Hz, 1H), 3.31 (s, 1H), 2.67 (s, 3H), 1.31-1.19 (m, 2H), 1.10-1.00 (m, 2H). 379 99% 2-19

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 9.28 (s, 1H), 8.93 (s, 1H), 8.70 (s, 1H), 8.36 (s, 1H), 8.03 (d, J = 8.65 Hz, 1H), 4.41 (s, 2H), 2.65 (s, 3H), 2.44 (s, 3H), 1.25 (d, J = 6.79 Hz, 2H), 1.10 (s, 2H). 420 97% 2-20

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 8.91 (s, 1H), 8.19 (d, J = 11.25 Hz, 3H), 7.99 (d, J = 8.83 Hz, 1H), 7.62 (s, 1H), 4.41 (s, 2H), 2.69 (s, 3H), 1.25 (d, J = 5.80 Hz, 2H), 1.05 (s, 2H). 397 99% 2-21

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.72 (s, 1H), 8.89 (s, 1H), 8.11-7.87 (m, 2H), 7.74 (s, 1H), 6.71 (s, 2H), 4.39 (s, 1H), 2.63 (d, J = 29.40 Hz, 3H), 1.20 (t, J = 25.86 Hz, 2H), 0.99 (d, J = 41.43 Hz, 2H). 388 98% 2-22

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.71 (s, 1H), 8.90 (s, 1H), 8.26 (s, 1H), 7.95 (d, J = 8.81 Hz, 1H), 7.86 (s, 1H), 6.89 (s, 2H), 4.39 (s, 1H), 2.66 (s, 3H), 1.24 (d, J = 5.61 Hz, 2H), 1.06 (s, 2H). 422 98% 2-23

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.71 (s, 1H), 8.98 (s, 1H), 8.13-8.02 (m, 2H), 7.92 (d, J = 14.79 Hz, 3H), 4.47 (s, 1H), 2.71 (d, J = 23.60 Hz, 3H), 2.31 (s, 3H), 1.29 (d, J = 5.54 Hz, 2H), 1.15 (d, J = 22.69 Hz, 2H). 368 99% 2-24

OMe Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.67 (s, 1H), 8.79 (s, 1H), 8.11 (s, 1H), 7.90 (s, 1H), 7.82 (s, 1H), 6.73 (s, 2H), 4.22 (s, 1H), 3.46 (s, 3H), 3.31 (s, 2H), 1.16 (s, 4H). 404 98% 2-25

OMe Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.66 (s, 1H), 8.80 (s, 1H), 8.39 (s, 1H), 8.13-7.81 (m, 2H), 6.91 (s, 2H), 4.23 (s, 1H), 3.31 (s, 3H), 1.17 (d, J = 6.99 Hz, 3H). 438 99% 2-26

OMe Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.74 (d, J = 61.68 Hz, 1H), 8.76 (d, J = 28.90 Hz, 1H), 8.39 (s, 1H), 7.97 (s, 1H), 7.92 (d, J = 9.13 Hz, 1H), 4.23 (s, 1H), 3.46 (s, 3H), 1.17 (d, J = 7.13 Hz, 4H). 395 98% 2-27

Me Cyclopropyl ¹H NMR (400 MHz, DMSO), δ 8.89 (s, 1H), 7.95- 7.93 (m, 2H), 7.83 (s, 1H), 7.60-6.57 (d, 1H), 4.39 (s, 1H), 2.63 (d, J = 29.40 Hz, 3H), 1.20 (t, J = 25.86 Hz, 2H), 0.99 (d, J =41.43 Hz, 2H). 372 98% 2-28

OMe Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 9.95 (s, 1H), 8.94- 8.66 (m, 1H), 8.49-8.39 (m, 1H), 8.26 (d, J = 1.30 Hz, 1H), 7.91 (dd, J = 19.79, 31.75 Hz, 2H), 4.27- 4.17 (m, 1H), 3.50-3.42 (m, 3H), 1.17 (dt, J = 7.59, 17.65 Hz, 3H). 398 98% 2-29

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 9.95 (s, 1H), 8.92 (d, J = 13.25 Hz, 1H), 8.32 (d, J = 1.05 Hz, 1H), 8.17 (d, J = 1.69 Hz, 1H), 8.00 (t, J = 18.18 Hz, 1H), 7.83 (d, J = 33.09 Hz, 1H), 4.40 (dt, J = 3.59, 10.71 Hz, 1H), 2.68 (d, J = 12.78 Hz, 3H), 1.25 (q, J = 6.89 Hz, 2H), 1.14-0.93 (m, 2H). 382 98% 2-30

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.64 (s, 2H), 8.90 (s, 1H), 7.97 (d, J = 8.81 Hz, 1H), 7.64 (d, J = 1.21 Hz, 1H), 7.34 (s, 1H), 4.40 (td, J = 3.75, 7.19 Hz, 1H), 3.90 (s, 3H), 2.78-2.61 (m, 3H), 1.23 (q, J = 7.19 Hz, 2H), 1.16-0.97 (m, 2H). 384 95% 2-31

Me

¹H NMR (400 MHz, DMSO) δ 14.64 (s, 2H), 8.90 (s, 1H), 7.97 (d, J = 8.81 Hz, 1H), 7.64 (d, J = 1.21 Hz, 1H), 7.34 (s, 1H), 4.40 (td, J = 3.75, 7.19 Hz, 1H), 3.90 (s, 3H), 2.78-2.61 (m, 3H), 1.23 (q, J = 7.19 Hz, 2H), 1.16-0.97 (m, 2H). 406 99% 2-32

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.62 (s, 1H), 8.90 (s, 1H), 7.99 (d, J = 1.60 Hz, 1H), 7.95 (t, J = 10.20 Hz, 1H), 7.70-7.53 (m, 1H), 4.39 (td, J = 3.61, 7.03 Hz, 1H), 2.62 (d, J = 19.25 Hz, 3H), 1.84 (ddd, J = 5.42, 8.33, 13.56 Hz, 1H), 1.21 (t, J = 6.56 Hz, 1H), 1.05 (d, J = 8.64 Hz, 1H), 1.03-0.96 (m, 2H), 0.78- 0.65 (m, 2H). 394 98% 2-33

Me

¹H NMR (400 MHz, DMSO) δ 8.88 (d, J = 3.01 Hz, 1H), 8.18 (s, 1H), 8.13 (s, 1H), 8.09 (s, 1H), 7.99 (d, J = 8.77 Hz, 1H), 7.54 (s, 1H), 5.29-5.01 (m, 1H), 4.50-4.31 (m, 1H), 2.71-2.57 (m, 2H), 1.76 (ddd, J = 9.04, 15.14, 17.62 Hz, 1H), 1.53 (d, J = 26.94 Hz, 1H). 415 98% 2-34

Cl Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 8.92 (s, 1H), 8.11 (d, J = 8.56 Hz, 1H), 8.02 (d, J = 0.96 Hz, 1H), 7.81 (d, J = 1.67 Hz, 1H), 4.44-4.39 (m, 2H), 1.32-1.17 (m, 2H), 1.17-1.04 (m, 2H). 408 94% 2-35

OMe Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 8.80 (s, 1H), 7.99 (s, 1H), 7.92 (d, J = 9.3 Hz, 1H), 7.69 (d, J = 12.0 Hz, 1H), 4.29-4.14 (m, 1H), 3.47 (s, 3H), 1.24- 1.04 (m, 4H). 387 99% 2-36

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.67 (s, 1H), 8.92 (s, 1H), 8.37 (s, 1H), 8.30 (d, J = 2.3 Hz, 1H), 8.11- 7.88 (m, 3H), 7.51 (s, 1H), 4.55-4.30 (m, 3H), 3.20 (m, 2H), 2.68 (s, 3H), 1.25 (d, J = 6.4 Hz, 2H), 1.08 (d, J = 7.0 Hz, 2H). 441 98% 2-37

OMe

¹H NMR (400 MHz, DMSO) δ 14.52 (s, 1H), 8.82 (d, J = 1.51 Hz, 1H), 8.38 (s, 1H), 8.11 (s, 1H), 7.94 (d, J = 9.20 Hz, 1H), 7.36 (s, 2H), 5.10 (ddd, J = 5.42, 8.45, 64.07 Hz, 1H), 4.24-4.12 (m, 1H), 1.86-1.55 (m, 2H). 413 98% 2-38

OMe

¹H NMR (400 MHz, DMSO) δ 14.55 (s, 1H), 8.82 (d, J = 1.46 Hz, 1H), 8.15 (d, J = 36.97 Hz, 1H), 7.92 (d, J = 9.24 Hz, 1H), 7.80 (s, 1H), 6.75 (s, 2H), 5.10 (ddd, J = 5.43, 8.45, 64.08 Hz, 1H), 4.29-4.12 (m, 1H), 1.93-1.53 (m, 2H). 422 98% 2-39

Me

¹H NMR (400 MHz, DMSO) δ 14.39 (s, 1H), 8.80 (s, 1H), 8.16-8.08 (m, 2H), 7.98-7.86 (m, 2H), 7.69- 7.59 (m, 1H), 7.37 (dd, J = 5.20, 11.82 Hz, 1H), 7.26 (s, 2H), 1.67 (s, 3H). 451 99% 2-40

Me Cyclopropyl ¹H NMR (400 MHz, CDCl₃) δ 14.60-14.29 (s, 1H), 8.96-8.89 (s, 1H), 8.05-7.96 (m, 2H), 7.48-7.40 (m, 4H), 7.40-7.33 (dt, J = 8.5, 2.8 Hz, 1H), 7.33-7.29 (s, 1H), 4.88-4.75 (s, 2H), 4.17-3.98 (s, 1H), 2.73- 2.62 (s, 3H), 1.28-1.20 (m, 2H), 1.02-0.93 (s, 2H). 430 99% 2-41

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.83-14.68 (s, 1H), 8.99-8.81 (s, 1H), 7.96-7.89 (d, J = 8.9 Hz, 1H), 7.88-7.81 (s, 1H), 7.36-7.20 (s, 1H), 6.19-6.08 (s, 2H), 4.47-4.31 (s, 1H), 2.75-2.60 (s, 3H), 1.36-1.10 (m, 6H), 1.10-0.94 (t, J = 3.1 Hz, 2H). 382 93% 2-42

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.83-14.67 (s, 3H), 8.97-8.85 (s, 3H), 8.00-7.85 (m, 6H), 7.72-7.60 (t, J = 1.7 Hz, 3H), 6.97-6.81 (dd, J = 17.3, 11.0 Hz, 3H), 6.45-6.27 (s, 6H), 5.85-5.70 (m, 4H), 5.44- 5.26 (dd, J = 11.0, 1.2 Hz, 3H), 4.47-4.33 (s, 1H), 2.76-2.60 (s, 9H), 1.30-1.18 (m, 6H), 1.12-0.98 (m, 5H), 1.32-1.20 (m, 7H). 380 99% 2-43

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 8.95-8.90 (s, 1H), 8.36-8.31 (m, 1H), 8.13-8.07 (d, J = 2.0 Hz, 1H), 8.02-7.97 (d, J = 8.8 Hz, 1H), 4.49-4.36 (m, 3H), 2.90-2.79 (s, 5H), 2.76-2.67 (s, 3H), 1.33-1.20 (q, J = 6.9 Hz, 2H), 1.10-0.98 (m, 2H). 397 98% 2-44

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 8.93-8.91 (s, 1H), 8.24-8.20 (m, 1H), 8.01-7.96 (d, J = 8.8 Hz, 1H), 7.93-7.87 (t, J = 2.8 Hz, 1H), 4.49-4.38 (tt, J = 7.2, 3.9 Hz, 1H), 4.24-4.14 (t, J = 5.5 Hz, 2H), 2.85-2.77 (s, 6H), 1.29-1.20 (m, 2H), 1.09- 0.98 (m, 2H). 411 97% 2-45

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 8.94-8.89 (s, 1H), 8.15-8.09 (d, J = 2.1 Hz, 1H), 8.02-7.96 (d, J = 8.9 Hz, 1H), 7.92-7.88 (s, 1H), 4.46-4.37 (m, 1H), 4.57- 4.46 (s, 2H), 2.71-2.65 (s, 3H), 1.25-1.18 (d, J = 6.7 Hz, 2H), 1.10-0.98 (m, 2H). 384 90% 2-46

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.71 (s, 1H), 8.89 (s, 1H), 8.35 (s, 2H), 7.94 (d, J = 8.67 Hz, 1H), 7.09 (s, 2H), 4.39 (s, 1H), 2.70 (s, 3H), 1.24 (d, J = 5.31 Hz, 2H), 1.03 (s, 2H). 354 99% 2-47

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.72 (s, 1H), 8.89 (s, 1H), 8.41 (s, 2H), 7.95 (d, J = 8.41 Hz, 1H), 7.60 (d, J = 28.12 Hz, 1H), 4.40 (s, 1H), 2.88 (s, 3H), 2.70 (s, 3H), 1.25 (d, J = 5.56 Hz, 2H), 1.03 (s, 2H). 369 99% 2-48

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.73 (s, 1H), 8.89 (s, 1H), 8.39 (s, 2H), 7.95 (d, J = 8.73 Hz, 1H), 7.64 (s, 1H), 4.39 (s, 1H), 2.70 (s, 3H), 2.53 (d, J = 9.32 Hz, 3H), 1.24 (d, J = 6.11 Hz, 2H), 1.17 (t, J = 6.98 Hz, 2H), 1.03 (s, 2H). 383 97% 2-49

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.72 (s, 2H), 8.90 (s, 1H), 8.48 (s, 2H), 7.96 (d, J = 8.59 Hz, 1H), 4.39 (s, 1H), 3.24 (d, J = 22.01 Hz, 6H), 2.70 (s, 3H), 1.25 (d, J = 6.03 Hz, 2H), 1.04 (d, J = 7.73 Hz, 2H). 383 98% 2-50

Cl Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 8.92 (s, 1H), 8.35 (s, 2H), 8.13 (d, J = 8.6 Hz, 1H), 7.15 (s, 2H), 4.41 (m, 3.8 Hz, 1H), 1.37-1.17 (m, 2H), 1.18-1.02 (m, 2H). 375 99% 2-51

Me

¹H NMR (400 MHz, DMSO) δ 8.87 (d, J = 3.2 Hz, 1H), 8.35 (d, J = 1.0 Hz, 2H), 7.97 (d, J = 8.9 Hz, 1H), 7.08 (s, 2H), 5.33-4.97 (m, 2H), 4.37 (m, 1H), 2.65 (s, 3H), 1.89-1.41 (m, 2H). 373 99% 2-52

MeO

¹H NMR (400 MHz, DMSO) δ 14.54 (s, 1H), 8.82 (d, J = 1.2 Hz, 1H), 8.44 (s, 2H), 7.93 (d, J = 9.2 Hz, 1H), 7.10 (s, 2H), 5.09 (m, 1H), 4.37-3.96 (m, 1H), 3.50 (s, 3H), 1.98-1.52 (m, 2H). 389 98% 2-53

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.65 (s, 1H), 8.91 (d, J = 4.9 Hz, 1H), 8.76 (s, 2H), 8.15-7.85 (m, 1H), 4.63-4.29 (m, 1H), 2.50 (s, 3H), 1.29- 1.15 (m, 2H), 1.06 (d, J = 7.0 Hz, 2H). 384 99% 2-54

MeO Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 8.86 (s, 1H), 8.52 (s, 2H), 8.00 (d, J = 9.2 Hz, 1H), 7.18 (s, 2H), 4.29 (m, 1H), 3.55 (s, 3H), 1.27-1.11 (m, 4H). 371 99% 2-55

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.67 (s, 1H), 8.79 (s, 1H), 8.19 (s, 1H), 7.90 (d, J = 9.3 Hz, 1H), 7.81 (s, 1H), 6.91 (t, J = 5.6 Hz, 1H), 4.29-4.11 (m, 1H), 3.53-3.41 (m, 5H), 1.26- 1.06 (m, 7H). 432 98% 2-56

¹H NMR (400 MHz, DMSO) δ 9.06 (s, 1H), 8.38 (s, 1H), 8.13 (d, J = 1.75 Hz, 1H), 7.72 (d, J = 9.80 Hz, 1H), 7.29 (s, 2H), 5.06-4.90 (m, 1H), 4.58 (d, J = 10.62 Hz, 1H), 4.44 (d, J = 9.71 Hz, 1H), 1.48 (d, J = 6.75 Hz, 3H). 381 95% 2-57

¹H NMR (400 MHz, DMSO) δ 14.95 (s, 1H), 8.91 (s, 1H), 8.37-8.33 (d, J = 2.5 Hz, 1H), 8.24-8.19 (d, J = 8.3 Hz, 1H), 8.14-8.10 (d, J = 2.5 Hz, 1H), 7.58-7.51 (d, J = 8.3 Hz, 1H), 7.22 (s, 2H), 4.42- 4.36 (tt, J = 7.1, 3.7 Hz, 1H), 2.71 (s, 3H), 1.30- 1.25 (m, 2H), 1.05-0.94 (m, 2H). 361 95% 2-58

¹H NMR (400 MHz, DMSO) δ 14.95 (s, 1H), 8.89 (s, 1H), 8.32 (d, J = 3.5 Hz, 1H), 8.21 (d, J = 8.2 Hz, 1H), 8.06 (s, 1H), 7.79 (s, 1H), 7.53 (d, J = 8.2 Hz, 1H), 6.61 (s, 2H), 4.39 (s, 1H), 2.72 (s, 3H), 1.27 (d, J = 6.1 Hz, 2H), 1.03 (s, 2H). 370 99% 2-59

¹H NMR (400 MHz, DMSO) δ 15.00 (s, 1H), 9.06 (s, 1H), 8.17 (s, 1H), 7.80 (s, 1H), 7.72 (d, J = 9.8 Hz, 1H), 6.86 (t, J = 5.7 Hz, 1H), 4.98 (d, J = 6.7 Hz, 1H), 4.57 (d, J = 10.2 Hz, 1H), 4.48-4.32 (m, 1H), 3.55-3.37 (m, 2H), 1.48 (d, J = 6.8 Hz, 2H), 1.17 (t, J = 7.1 Hz, 2H). 418 98% 2-60

¹H NMR (400 MHz, DMSO) δ 14.55 (s, 1H), 8.82 (d, J = 1.6 Hz, 1H), 8.18 (s, 1H), 7.92 (d, J = 9.3 Hz, 1H), 7.80 (s, 1H), 6.92 (t, J = 5.7 Hz, 1H), 5.10 (ddd J = 64.1, 8.4, 5.4 Hz, 1H), 4.32-4.06 (m, 1H), 3.58-3.37 (m, 5H), 1.93-1.51 (m, 2H), 1.19 (t, J = 7.1 Hz, 3H). 450 98%

TABLE 3

Com - pound MS No. R³ = R² = R¹ = NMR (MH⁺) HPLC 3-1

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.59 (s, 1H), 9.08 (s, 1H), 8.94 (s, 1H), 8.33 (d, J = 1.3 Hz, 1H), 8.16 (d, J = 1.7 Hz, 1H), 8.06 (t, J = 8.5 Hz, 2H), 7.85 (d, J = 9.4 Hz, 1H), 4.49-4.38 (m, 1H), 2.70 (s, 3H), 1.25 (d, J = 6.6 Hz, 2H), 1.09 (s, 2H). 378 98% 3-2

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.63 (s, 1H), 9.38 (s, 1H), 8.91 (d, J = 25.3 Hz, 1H), 8.79 (s, 1H), 8.13 (s, 1H), 8.06 (d, J = 8.8 Hz, 1H), 8.01 (s, 1H), 4.44 (s, 1H), 2.75 (s, 3H), 1.25 (s, 2H), 1.09 (s, 2H). 379 95% 3-3

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.70 (s, 1H), 9.41 (s, 1H), 9.00 (s, 1H), 8.80 (s, 1H), 8.36 (s, 1H), 8.17 (s, 1H), 8.07 (s, 2H), 7.86 (s, 1H), 7.61 (s, 1H), 4.49 (s, 1H), 2.79 (s, 3H), 1.31 (s, 3H), 1.17 (s, 2H). 456 98% 3-4

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.57 (d, J = 5.1 Hz, 1H), 9.05 (d, J = 6.5 Hz, 1H), 8.94 (s, 1H), 8.44 (s, 1H), 8.23 (s, 1H), 8.11 (s, 1H), 8.05 (d, J = 8.8 Hz, 1H), 7.54 (d, J = 6.4 Hz, 1H), 4.43 (s, 1H), 2.68 (s, 3H), 1.24 (d, J = 5.0 Hz, 2H), 1.11 (s, 2H). 378 97% 3-5

OMe Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.64 (s, 1H), 9.13 (d, J = 6.3 Hz, 1H), 8.90 (s, 1H), 8.53 (s, 1H), 8.31 (d, J = 11.7 Hz, 2H), 8.09 (d, J = 9.1 Hz, 1H), 7.72 (d, J = 5.8 Hz, 1H), 4.30 (s, 1H), 3.57 (s, 3H), 1.25 (s, 4H). 394 95% 3-6

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 9.30 (s, 1H), 8.93 (s, 1H), 8.64 (s, 1H), 8.04 (t, J = 9.2 Hz, 2H), 7.75 (d, J = 9.2 Hz, 1H), 4.42 (s, 1H), 2.69 (s, 3H), 1.24 (s, 2H), 1.09 (s, 2H). 379 97% 3-7

OMe Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.61 (s, 1H), 9.33 (s, 1H), 8.83 (s, 1H), 8.64 (s, 1H), 8.06 (d, J = 9.2 Hz, 1H), 8.01 (d, J = 9.1 Hz, 1H), 7.86 (d, J = 9.3 Hz, 1H), 4.24 (s, 1H), 3.48 (s, 3H), 1.19 (d, J = 5.2 Hz, 4H). 395 98% 3-8

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.60 (s, 1H), 9.11 (s, 1H), 8.93 (s, 1H), 8.22 (d, J = 1.2 Hz, 1H), 8.17 (s, 1H), 8.03 (d, J = 8.9 Hz, 1H), 7.84 (d, J = 1.1 Hz, 1H), 4.43 (tt, J = 7.1, 3.7 Hz, 1H), 2.70 (s, 3H), 1.26 (d, J = 6.8 Hz, 2H), 1.09 (s, 2H). 379 98% 3-9

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.60 (s, 1H), 9.07 (s, 1H), 8.93 (s, 1H), 8.22 (s, 1H), 8.02 (d, J = 8.9 Hz, 1H), 7.81 (s, 1H), 7.80 (s, 1H), 4.49-4.37 (m, 1H), 2.70 (d, J = 21.5 Hz, 3H), 1.27 (t, J = 9.8 Hz, 2H), 1.14-1.05 (m, 2H). 446 97% 3-10

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.62 (s, 1H), 8.94 (s, 2H), 8.35 (s, 1H), 8.23 (s, 1H), 8.05 (d, J = 8.7 Hz, 1H), 7.75 (s, 1H), 4.43 (s, 1H), 2.69 (s, 3H), 2.66 (s, 3H), 1.24 (s, 2H), 1.08 (s, 2H). 392 98% 3-11

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.61 (s, 1H), 8.92 (s, 1H), 8.79 (d, J = 1.2 Hz, 1H), 8.16 (d, J = 1.1 Hz, 1H), 8.01 (d, J = 8.8 Hz, 1H), 7.76 (d, J = 1.1 Hz, 1H), 7.58 (s, 1H), 4.42 (tt, J = 7.2, 3.8 Hz, 1H), 2.70 (d, J = 20.2 Hz, 3H), 1.26 (d, J = 6.9 Hz, 2H), 1.15-1.03 (m, 2H). 412 99% 3-12

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 9.40 (s, 1H), 8.94 (s, 1H), 8.88 (s, 1H), 8.18 (d, J = 9.3 Hz, 1H), 8.05 (d, J = 8.8 Hz, 1H), 7.89 (d, J = 9.3 Hz, 1H), 4.43 (s, 1H), 2.69 (s, 3H), 1.24 (d, J = 6.1 Hz, 2H), 1.12 (s, 2H). 423 96% 3-13

OMe Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.60 (s, 1H), 8.90 (s, 1H), 8.83 (s, 1H), 8.22 (d, J = 1.0 Hz, 1H), 7.98 (d, J = 9.2 Hz, 1H), 7.75 (d, J = 1.0 Hz, 1H), 7.66 (s, 1H), 4.29- 4.18 (m, 1H), 3.51 (d, J = 13.2 Hz, 3H), 1.25-1.14 (m, 4H). 428 100% 3-14

OMe Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.59 (s, 1H), 9.19 (s, 1H), 8.83 (s, 1H), 8.28 (s, 1H), 8.01 (d, J = 9.2 Hz, 1H), 7.92 (s, 1H), 7.81 (s, 1H), 4.25 (dt, J = 11.0, 5.7 Hz, 1H), 3.50 (d, J = 12.8 Hz, 3H), 1.19 (m, 4H). 462 98% 3-15

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 9.61 (s, 1H), 8.93 (s, 1H), 8.51 (s, 1H), 8.13 (s, 1H), 8.04 (d, J = 8.8 Hz, 1H), 7.97 (d, J = 9.2 Hz, 1H), 7.62 (d, J = 9.2 Hz, 1H), 7.55 (s, 1H), 4.42 (s, 1H), 2.69 (s, 3H), 1.24 (s, 2H), 1.10 (s, 2H). 421 98% 3-16

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.87-13.95 (m, 2H), 9.60 (s, 1H), 8.94 (s, 1H), 8.44 (s, 1H), 8.05 (t, J = 9.5 Hz, 2H), 7.71 (d, J = 9.4 Hz, 1H), 4.46-4.39 (m, 1H), 2.71 (m, 3H), 2.46 (s, 3H), 1.25 (d, J = 6.3 Hz, 2H), 1.11 (s, 2H). 459 98% 3-17

Cl Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.44-13.91 (m, 1H), 9.16 (s, 1H), 8.95 (s, 1H), 8.37 (s, 1H), 8.23 (d, J = 8.6 Hz, 1H), 8.08 (s, 1H), 7.81 (s, 1H), 4.43 (m, 1H), 1.23 (m, 2H), 1.16 (s, 2H). 398 98% 3-18

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.62 (s, 1H), 8.92 (s, 1H), 8.68 (s, 1H), 8.19 (d, J = 2.9 Hz, 1H), 8.01 (d, J = 8.8 Hz, 1H), 7.73 (d, J = 1.0 Hz, 1H), 7.32 (d, J = 11.7 Hz, 1H), 4.42 (m, 1H), 2.72 (s, 3H), 1.25 (d, 2H), 1.12-1.04 (m, 2H). 396 98% 3-19

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 9.29 (s, 1H), 8.94 (s, 1H), 8.54 (s, 1H), 8.36 (s, 1H), 8.05 (d, J = 8.9 Hz, 1H), 8.00 (s, 1H), 4.49-4.38 (m, 1H), 2.74 (s, 3H), 1.25 (d, J = 6.9 Hz, 2H), 1.11 (s, 2H). 423 98% 3-20

Cl Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 8.95 (s, 1H), 8.88 (t, J = 4.2 Hz, 1H), 8.22 (t, J = 2.4 Hz, 1H), 8.20 (d, J = 8.5 Hz, 1H), 7.82 (s, 1H), 7.68 (s, 1H), 4.48-4.36 (m, 1H), 1.26-1.19 (m, 2H), 1.14 (m, 2H). 432 98% 3-21

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.60 (s, 1H), 9.32 (d, J = 1.2 Hz, 1H), 8.93 (s, 1H), 8.71 (s, 1H), 8.06 (s, 1H), 8.02 (d, J = 8.8 Hz, 1H), 4.43 (tt, J = 7.0, 3.6 Hz, 1H), 2.70 (d, J = 17.8 Hz, 3H), 1.30-1.20 (m, 2H), 1.15-1.05 (m, 2H). 413 98% 3-22

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.57 (s, 1H), 9.22 (s, 1H), 8.93 (s, 1H), 8.71 (s, 1H), 8.02 (d, J = 8.8 Hz, 1H), 7.85 (d, J = 10.8 Hz, 1H), 4.47-4.37 (m, 1H), 2.72 (s, 3H), 1.29-1.22 (m, 2H), 1.10 (s, 2H). 397 99% 3-23

OMe Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.57 (s, 1H), 9.26 (s, 1H), 8.84 (s, 1H), 8.72 (s, 1H), 8.01 (d, J = 9.1 Hz, 1H), 7.92 (d, J = 10.9 Hz, 1H), 4.28-4.18 (m, 1H), 3.51 (s, 3H), 1.20 (d, J = 5.5 Hz, 4H). 413 95% 3-24

OMe

¹H NMR (400 MHz, DMSO) δ 14.47 (s, 1H), 8.89 (t, J = 1.3 Hz, 1H), 8.86 (d, J = 1.8 Hz, 1H), 8.23 (d, J = 1.3 Hz, 1H), 8.00 (d, J = 9.1 Hz, 1H), 7.75 (d, J = 1.2 Hz, 1H), 7.63 (t, J = 1.3 Hz, 1H), 5.31-4.93 (dtd, J = 64.0, 5.5, 3.3 Hz, 1H), 4.26-4.12 (dt, J = 8.9, 5.4 Hz, 1H), 3.54 (s, 3H), 1.93-1.49 (m, 2H). 446 98% 3-25

Me

¹H NMR (400 MHz, CDCl₃) δ 14.07 (s, 1H), 8.55 (s, 1H), 8.14 (d, J = 8.4 Hz, 1H), 8.00 (d, J = 17.0 Hz, 1H), 7.66 (dd, J = 11.6, 4.8 Hz, 2H), 7.49 (d, J = 4.4 Hz, 1H), 7.13-7.03 (m, 2H), 7.01 (d, J = 0.8 Hz, 1H), 5.22 (s, 1H), 1.72 (s, 3H). 484 98% 3-26

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.64 (s, 1H), 9.09 (s, 1H), 8.93 (s, 1H), 8.58 (s, 1H), 8.02 (d, J = 8.8 Hz, 1H), 7.54 (s, 1H), 4.46-4.36 (m, 1H), 2.70 (s, 3H), 2.64 (s, 3H), 1.25 (d, J = 6.2 Hz, 2H), 1.09 (s, 2H). 393 98% 3-27

Me

¹H NMR (400 MHz, DMSO) δ 14.48 (s, 1H), 8.90 (d, J = 3.0 Hz, 1H), 8.78 (s, 1H), 8.16 (s, 1H), 8.03 (d, J = 8.8 Hz, 1H), 7.75 (s, 1H), 7.57 (s, 1H), 5.16 (d, J = 64.5 Hz, 1H), 4.44-4.33 (m, 1H), 2.65 (s, 3H), 1.83-1.68 (m, 1H), 1.62 (m, 1H). 430 98% 3-28

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.59 (s, 1H), 9.63 (s, 1H), 8.94 (s, 1H), 8.81 (s, 1H), 8.30 (s, 1H), 8.04 (d, J = 8.9 Hz, 1H), 4.50-4.37 (m, 1H), 2.73 (s, 3H), 1.24 (t, J = 9.6 Hz, 2H), 1.12 (s, 2H). 447 98% 3-29

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 9.33 (s, 1H), 8.94 (s, 1H), 8.74 (s, 1H), 8.63 (s, 2H), 8.05 (d, J = 8.8 Hz, 1H), 7.84 (s, 1H), 4.51 (s, 2H), 4.46-4.36 (m, 1H), 2.71 (s, 3H), 1.26 (d, J = 6.8 Hz, 2H), 1.09 (s, 2H). 408 95% 3-30

OMe Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.58 (s, 1H), 9.37 (s, 1H), 8.84 (s, 1H), 8.72 (s, 1H), 8.13 (s, 1H), 8.00 (d, J = 9.0 Hz, 1H), 4.29-4.18 (m, 1H), 3.51 (s, 3H), 1.20 (d, J = 5.4 Hz, 4H). 429 96% 3-31

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 9.43 (s, 1H), 8.99 (s, 1H), 8.89 (s, 1H), 8.14-8.01 (m, 2H), 7.54 (d, J = 9.8 Hz, 1H), 4.49 (s, 2H), 2.77 (s, 3H), 1.30 (s, 2H), 1.14 (s, 2H). 379 88% 3-32

OMe Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 9.42 (s, 1H), 8.92 (s, 1H), 8.83 (s, 1H), 8.00 (s, 2H), 7.57 (d, J = 9.3 Hz, 1H), 4.23 (s, 1H), 3.51 (s, 3H), 1.18 (s, 4H). 395 95% 3-33

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 8.98 (s, 1H), 8.74 (s, 1H), 8.48 (s, 1H), 8.23 (s, 1H), 8.04 (d, J = 8.9 Hz, 1H), 4.39 (s, 2H), 2.64 (s, 3H), 1.29 (s, 2H), 1.07 (s, 2H). 379 99% 3-34

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 15.02-14.73 (m, 1H), 9.01 (s, 1H), 8.10 (s, 3H), 7.54 (s, 1H), 4.51 (s, 1H), 1.33 (s, 2H), 1.18 (s, 2H). 379 95% 3-35

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.68 (s, 1H), 14.19 (s, 1H), 8.93 (s, 1H), 8.53 (s, 1H), 8.44 (s, 1H), 8.40 (s, 1H), 8.01 (d, J = 8.5 Hz, 1H), 4.42 (s, 1H), 2.64 (s, 3H), 1.22 (m, 2H), 1.12 (m, 2H). 423 98% 3-36

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 12.87 (s, 1H), 8.97 (s, 1H), 8.10 (s, 1H), 8.01 (d, J = 8.7 Hz, 1H), 7.02 (s, 1H), 6.48 (s, 1H), 4.46 (s, 1H), 2.70 (s, 2H), 1.30 (s, 2H), 1.12 (s, 2H). 393 98% 3-37

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.83 (s, 1H), 13.45 (b, 1H), 8.98 (s, 1H), 8.26 (s, 1H), 8.04 (d, J = 8.6 Hz, 1H), 7.90 (s, 1H), 7.78 (d, J = 8.5 Hz, 1H), 7.42 (d, J = 8.4 Hz, 1H), 4.46 (s, 1H), 2.68 (s, 3H), 1.31 (d, J = 5.7 Hz, 2H), 1.14 (s, 2H). 378 92% 3-38

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.69 (s, 1H), 13.83 (s, 1H), 8.91 (s, 1H), 8.31 (s, 1H), 7.98 (d, J = 8.8 Hz, 1H), 7.83 (s, 1H), 7.53 (s, 1H), 4.46-4.34 (m, 1H), 2.63 (s, 3H), 1.25 (d, J = 6.9 Hz, 2H), 1.09 (s, 2H). 412 98% 3-39

OMe Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.74 (s, 1H), 14.27 (s, 1H), 8.90 (s, 1H), 8.62 (d, J = 10.6 Hz, 3H), 8.07 (d, J = 9.1 Hz, 1H), 4.31 (s, 1H), 3.44 (s, 3H), 1.26 (s, 4H). 439 95% 3-40

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.77 (s, 1H), 13.23 (s, 1H), 8.91 (s, 1H), 8.49 (s, 1H), 7.98 (d, J = 8.3 Hz, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.67 (s, 1H), 7.25 (d, J = 7.9 Hz, 1H), 4.40 (s, 1H), 2.61 (s, 2H), 1.25 (s, 2H), 1.09 (s, 2H). 378 98% 3-41

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.72 (s, 1H), 9.52 (s, 1H), 8.92 (s, 1H), 8.30 (s, 1H), 8.27 (d, J = 8.4 Hz, 1H), 8.01 (d, J = 8.8 Hz, 1H), 7.58 (d, J = 8.1 Hz, 1H), 4.40 (s, 1H), 2.62 (s, 3H), 1.25 (d, J = 5.9 Hz, 2H), 1.08 (s, 2H). 395 95% 3-42

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.77 (s, 1H), 11.96 (s, 1H), 8.92 (s, 1H), 8.24 (s, 1H), 8.06 (s, 1H), 7.99 (d, J = 8.7 Hz, 1H), 7.61 (s, 1H), 6.57 (s, 1H), 4.41 (s, 1H), 2.64 (s, 3H), 1.26 (d, J = 6.1 Hz, 2H), 1.09 (s, 2H). 378 98% 3-43

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.76-14.48 (s, 1H), 8.97-8.90 (d, J = 2.7 Hz, 2H), 8.63-8.55 (s, 1H), 8.07-7.97 (t, J = 9.2 Hz, 2H), 7.69-7.58 (m, 1H), 4.48-4.39 (s, 2H), 2.73-2.65 (s, 3H), 1.27-1.20 (m, 2H), 1.14-1.06 (s, 2H). 403 95% 3-44

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 10.02-9.98 (s, 1H), 9.48-8.43 (s, 1H), 8.95-8.90 (s, 1H), 8.67-8.62 (s, 1H), 8.12-8.07 (d, J = 9.2 Hz, 1H), 8.07-8.01 (d, J = 8.9 Hz, 1H), 7.82-7.75 (dd, J = 9.4, 1.7 Hz, 1H), 4.48-4.36 (s, 1H), 2.72-2.67 (s, 3H), 1.25-1.21 (t, J = 3.8 Hz, 2H), 1.14-1.06 (m, 2H). 406 90% 3-45

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 9.93 (s, 1H), 8.83 (s, 1H), 8.40 (s, 1H), 8.09-8.05 (dd, J = 9.2, 1.0 Hz, 1H), 8.05-8.00 (d, J = 8.7 Hz, 1H), 7.81-7.72 (dd, J = 9.3, 1.7 Hz, 1H), 5.35-5.16 (s, 1H), 4.53-4.33 (m, 1H), 2.75-2.64 (s, 3H), 1.28- 1.20 (d, J = 6.2 Hz, 2H), 1.15-1.03 (d, J = 3.8 Hz, 2H). 402 98% 3-46

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.70-14.56 (s, 1H), 9.23-9.15 (m, 1H), 8.99- 8.89 (s, 1H), 8.72-8.65 (s, 1H), 8.08-7.99 (d, J = 8.8 Hz, 1H), 7.84-7.77 (s, 1H), 7.16-7.04 (m, 1H), 6.93-6.82 (m, 1H), 5.82-5.69 (dd, J = 11.2, 1.6 Hz, 1H), 4.49-4.36 (t, J = 3.5 Hz, 1H), 2.75-2.68 (s, 3H), 1.33-1.19 (t, J = 6.5 Hz, 2H), 1.16-1.03 (s, 2H). 405 97% 3-47

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.76-14.48 (s, 1H), 8.96-8.91 (s, 4H), 8.86-8.79 (s, 4H), 8.64-8.56 (d, J = 2.3 Hz, 4H), 8.06-7.99 (d, J = 8.8 Hz, 4H), 7.86-7.79 (d, J = 9.4 Hz, 4H), 7.52-7.43 (s, 3H), 4.48-4.37 (s, 1H), 2.74-2.67 (s, 12H), 1.29-1.20 (d, J = 6.8 Hz, 9H), 1.11-1.01 (t, J = 3.0 Hz, 6H). 422 96% 3-48

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.76-14.48 (s, 1H), 8.95-8.89 (s, 1H), 8.84-8.78 (s, 1H), 8.63-8.58 (s, 1H), 8.05-8.00 (d, J = 8.8 Hz, 1H), 7.90-7.84 (d, J = 9.4 Hz, 1H), 7.53-7.45 (d, J = 9.3 Hz, 1H), 4.47-4.40 (s, 1H), 2.73-2.68 (s, 3H), 1.27-1.21 (d, J = 6.6 Hz, 2H), 1.12-1.02 (s, 2H). 446 90% 3-49

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 8.93 (s, 1H), 8.66 (s, 1H), 8.06-7.99 (d, J = 8.7 Hz, 1H), 7.99-7.95 (s, 1H), 7.94-7.88 (d, J = 9.3 Hz, 1H), 7.55-7.47 (dd, J = 9.3, 1.6 Hz, 1H), 4.52-4.32 (m, 1H), 2.77-2.61 (s, 3H), 1.33-1.17 (d, J = 6.6 Hz, 2H), 1.19-1.05 (t, J = 3.3 Hz, 2H). 412 98% 3-50

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 8.93 (s, 1H), 8.60 (s, 1H), 8.06-8.00 (d, J = 8.7 Hz, 1H), 8.00-7.96 (s, 1H), 7.92-7.86 (d, J = 9.3 Hz, 1H), 7.56-7.48 (d, J = 9.4 Hz, 1H), 4.55-4.26 (m, 1H), 2.81-2.60 (s, 3H), 1.37-1.21 (d, J = 6.5 Hz, 2H), 1.15-1.05 (m, 2H). 456, 458 97% 3-51

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.71-14.62 (s, 1H), 8.96-8.88 (s, 1H), 8.83-8.75 (s, 1H), 8.25-8.16 (d, J = 7.5 Hz, 2H), 8.15-8.07 (s, 1H), 8.07-7.97 (d, J = 8.8 Hz, 1H), 7.77-7.71 (s, 1H), 7.57-7.42 (m, 4H), 4.50-4.33 (s, 1H), 2.82-2.71 (s, 3H), 1.31-1.22 (d, J = 6.7 Hz, 2H), 1.15-1.04 (s, 2H). 454 99% 3-52

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.71-14.60 (s, 1H), 8.95-8.88 (s, 1H), 8.73-8.65 (s, 1H), 8.10-7.96 (m, 2H), 7.74-7.68 (s, 1H), 7.40-7.32 (s, 1H), 7.11-7.02 (m, 1H), 6.96-6.83 (m, 1H), 5.70-5.60 (dd, J = 11.2, 2.0 Hz, 1H), 4.47-4.38 (t, J = 3.5 Hz, 1H), 2.78-2.69 (s, 3H), 1.31-1.20 (d, J = 6.9 Hz, 2H), 1.14-1.01 (s, 2H). 405 93% 3-53

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.71-14.60 (s, 1H), 8.95-8.88 (s, 1H), 8.73-8.65 (s, 1H), 8.10-7.96 (m, 2H), 7.74-7.68 (s, 1H), 7.40-7.32 (s, 1H), 7.11-7.02 (m, 1H), 6.96-6.83 (m, 1H), 5.70-5.60 (dd, J = 11.2, 2.0 Hz, 1H), 4.47-4.38 (t, J = 3.5 Hz, 1H), 2.78-2.69 (s, 3H), 1.31-1.20 (d, J = 6.9 Hz, 2H), 1.14-1.01 (s, 2H). 403 95% 3-54

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.76-14.39 (s, 1H), 9.20-9.07 (d, J = 7.0 Hz, 1H), 8.95-8.90 (s, 1H), 8.67-8.60 (s, 1H), 8.08-8.00 (m, 2H), 7.32-7.24 (m, 1H), 4.47-4.36 (s, 1H), 2.75-2.61 (s, 3H), 1.30-1.19 (m, 2H), 1.15-1.03 (q, J = 3.8, 3.1 Hz, 2H). 379 98% 3-55

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.76-14.36 (s, 1H), 9.68-9.65 (d, J = 1.5 Hz, 1H), 8.95-8.92 (s, 1H), 8.84-8.81 (s, 1H), 8.63-8.59 (d, J = 1.5 Hz, 1H), 8.06-8.01 (d, J = 8.8 Hz, 1H), 4.46-4.39 (s, 1H), 2.76-2.69 (s, 3H), 1.30-1.20 (m, 2H), 1.14-1.05 (s, 2H). 404 98% 3-56

OMe

¹H NMR (400 MHz, DMSO) δ 14.73-14.06 (s, 1H), 9.21-9.18 (m, 1H), 8.87-8.83 (d, J = 1.86 Hz, 1H), 8.32-8.27 (d, J = 1.33 Hz, 1H), 8.20-8.16 (s, 1H), 8.04-7.97 (d, J = 9.06 Hz, 1H), 7.87-7.80 (d, J = 1.20 Hz, 1H), 5.31-4.87 (m, 1H), 4.32-4.12 (m, 1H), 3.67-3.47 (s, 3H), 1.95-1.56 (m, 2H). 437 98% 3-57

OMe Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.61 (s, 1H), 8.83 (s, 1H), 8.77 (s, 1H), 8.23 (d, J = 2.1 Hz, 1H), 7.99 (d, J = 9.2 Hz, 1H), 7.73 (d, J = 1.0 Hz, 1H), 7.40 (d, J = 11.8 Hz, 1H), 4.46-4.08 (m, 1H), 3.51 (d, J = 10.5 Hz, 3H), 1.19 (d, J = 6.9 Hz, 4H). 412 90% 3-58

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.83-14.57 (s, 1H), 9.82-9.48 (s, 2H), 9.01-8.84 (d, J = 2.6 Hz, 1H), 8.05-7.90 (dd, J = 8.5, 2.7 Hz, 1H), 7.65-7.57 (d, J = 7.5 Hz, 1H), 7.51-7.46 (s, 1H), 7.45-7.36 (d, J = 7.7 Hz, 1H), 4.72-4.50 (s, 4H), 4.47- 4.28 (d, J = 6.8 Hz, 1H), 2.64-2.53 (d, J = 2.7 Hz, 379 95% 3H), 1.31-1.14 (d, J = 6.1 Hz, 2H), 1.14-0.96 (s, 2H). 3-59

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 8.95-8.83 (d, J = 2.4 Hz, 1H), 7.98-7.86 (d, J = 8.8 Hz, 1H), 7.25-7.15 (s, 1H), 7.14-7.01 (d, J = 7.9 Hz, 1H), 6.97-6.81 (d, J = 7.9 Hz, 1H), 3.65-3.50 (m, 2H), 4.45-4.29 (dp, J = 9.2, 4.7, 3.9 Hz, 1H), 3.16-2.99 (t, J = 8.4 Hz, 2H), 2.65-2.56 (s, 3H), 1.28-1.16 (d, 379 99% J = 6.6 Hz, 3H), 1.12-0.97 (m, 2H). 3-60

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 15.01-14.39 (m, 1H), 12.95-12.53 (s, 2H), 9.03-8.82 (t, J = 1.9 Hz, 1H), 8.73-8.47 (s, 2H), 8.10-7.90 (d, J = 8.4 Hz, 1H), 7.62-7.44 (m, 1H), 4.51-4.23 (m, 1H), 7.44-7.31 (s, 1H), 7.31-7.11 (d, J = 8.6 Hz, 1H), 2.65-2.55 (s, 3H), 1.30-1.16 (m, 2H), 1.16-0.96 (s, 2H). 393 90% 3-61

Me Cyclopropyl ¹H NMR (400 MHz, MeOD) δ 9.17-9.06 (d, J = 2.8 Hz, 1H), 8.30-8.15 (m, 1H), 7.94-7.80 (m, 2H), 7.65-7.49 (dt, J = 7.5, 3.3 Hz, 2H), 4.47-4.32 (d, J = 6.9 Hz, 1H), 2.96-2.81 (d, J = 2.8 Hz, 3H), 1.43-1.27 (dd, J = 10.8, 4.5 Hz, 2H), 1.21-1.05 (s, 2H). 378 100% 3-62

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.63-14.42 (s, 1H), 8.99-8.89 (s, 1H), 8.33-8.25 (d, J = 7.8 Hz, 1H), 8.25-8.18 (d, J = 8.0 Hz, 1H), 8.14-8.05 (d, J = 8.7 Hz, 1H), 7.71-7.56 (dt, J = 22.8, 7.4 Hz, 2H), 4.51-4.31 (s, 1H), 395 100% 2.85-2.70 (s, 3H), 1.30-1.20 (d, J = 7.0 Hz, 2H), 1.13-0.97 (s, 2H). 3-63

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 15.01-14.28 (s, 2H), 9.04-8.82 (t, J = 2.3 Hz, 1H), 8.50-7.98 (d, J = 8.3 Hz, 1H), 7.98-7.92 (dd, J = 10.5, 2.5 Hz, 1H), 7.90-7.83 (s, 1H), 7.56-7.47 (d, J = 8.2 Hz, 1H), 4.46-4.34 (t, J = 6.3 Hz, 1H), 2.87-2.78 (t, J = 2.1 Hz, 3H), 2.64-2.55 (s, 3H), 1.29-1.16 (m, 2H), 392 100% 1.16-1.03 (s, 2H). 3-64

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 15.01-14.28 (s, 2H), 9.04-8.82 (t, J = 2.3 Hz, 1H), 8.05-7.98 (d, J = 8.3 Hz, 1H), 7.98-7.92 (dd, J = 10.5, 2.5 Hz, 1H), 7.90-7.83 (s, 1H), 7.56-7.47 (d, J = 8.2 Hz, 1H), 4.46-4.34 (t, J = 6.3 Hz, 1H), 2.87-2.78 (t, J = 2.1 Hz, 3H), 2.64-2.55 (m, 6H), 1.29-1.16 (m, 2H), 1.16-1.03 (s, 2H). 421 100% 3-65

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 15.05-14.35 (m, 1H), 10.46-9.91 (m, 1H), 9.02- 8.80 (s, 1H), 8.80-8.47 (d, J = 15.2 Hz, 1H), 8.12-7.64 (m, 3H), 7.44-7.25 (dd, J = 23.7, 8.0 Hz, 1H), 4.84-4.63 (d, J = 8.8 Hz, 2H), 4.49-4.32 (s, 1H), 3.01-2.77 (d, J = 17.9 Hz, 6H), 1.37-1.13 (d, J = 6.9 Hz, 2H), 1.17-0.86 (s, 2H). 449 96% 3-66

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.97-14.24 (s, 2H), 9.14-8.97 (m, 2H), 8.98-8.88 (s, 2H), 8.07-7.89 (dd, J = 24.1, 8.9 Hz, 6H), 7.86-7.79 (s, 1H), 7.52-7.37 (t, J = 9.6 Hz, 3H), 4.57-4.31 (t, J = 6.8 Hz, 5H), 2.66-2.55 (s, 7H), 1.60-1.40 (m, 7H), 1.30-1.16 (m, 2H), 1.16-0.98 (s, 2H). 406 97% 3-67

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.97-14.24 (s, 2H), 9.14-8.97 (m, 2H), 8.98- 8.88 (s, 2H), 8.07-7.89 (dd, J = 24.1, 8.9 Hz, 6H), 7.86-7.79 (s, 1H), 7.52-7.37 (t, J = 9.6 Hz, 3H), 4.57-4.31 (t, J = 6.8 Hz, 5H), 2.66-2.55 (s, 3H), 1.60-1.40 (m, 7H), 1.30-1.16 (m, 2H), 1.16-0.98 (s, 2H). 392 100% 3-68

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 8.95-8.91 (s, 1H), 8.65-8.59 (s, 1H), 8.31-8.25 (s, 1H), 8.23-8.17 (s, 1H), 8.05-7.98 (m, 1H), 4.48-4.35 (s, 1H), 2.68-2.61 (s, 3H), 1.30-1.22 (s, 2H), 1.16-1.06 (s, 2H). 423 97% 3-69

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.96-14.48 (m, 1H), 10.94-10.65 (d, J = 25.6 Hz, 2H), 9.01-8.77 (m, 1H), 8.05-7.81 (d, J = 8.6 Hz, 1H), 7.18-7.00 (d, J = 7.8 Hz, 1H), 7.00-6.78 (m, 2H), 4.47-4.25 (td, J = 6.9, 3.6 Hz, 1H), 2.67-2.54 (s, 3H), 1.27-1.10 (d, J = 6.3 Hz, 2H), 1.14-0.88 (s, 2H). 394 94% 3-70

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 15.02-14.18 (s, 1H), 9.00-8.67 (m, 2H), 8.12-7.68 (m, 3H), 7.49-7.25 (dd, J = 16.6, 8.2 Hz, 1H), 5.04-4.75 (m, 1H), 4.62- 4.23 (m, 9H), 3.77-3.55 (m, 2H), 3.57-3.23 (d, J = 7.0 Hz, 1H), 2.70-2.53 (s, 3H), 1.37-1.15 (t, J = 8.0 Hz, 2H), 1.15-0.84 (td, J = 16.0, 7.8 Hz, 9H). 494 90% 3-71

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.45-14.13 (s, 1H), 11.09-10.85 (s, 1H), 8.73- 8.58 (d, J = 2.7 Hz, 1H), 7.85-7.61 (m, 2H), 7.31-7.15 (m, 1H), 7.07-6.83 (m, 2H), 4.27-4.07 (s, 1H), 3.82-3.71 (d, J = 2.5 Hz, 3H), 1.27-1.08 (m, 2H), 1.08-0.86 (s, 2H). 408 93% 3-72

OMe Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 15.07-14.72 (s, 1H), 9.21-8.97 (s, 1H), 8.95-8.73 (m, 1H), 8.41-8.14 (m, 1H), 8.12-7.95 (s, 1H), 3.40-3.18 (m, 4H), 7.95-7.79 (d, J = 8.6 Hz, 1H), 7.79-7.60 (dd, J = 8.5, 3.9 Hz, 2H), 4.34-4.10 (d, J = 6.3 Hz, 1H), 1.30-1.02 (s, 4H). 376 95% 3-73

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.85-14.61 (s, 1H), 10.68-10.51 (s, 1H), 9.04-8.78 (m, 1H), 8.01-7.81 (m, 1H), 7.36-7.11 (m, 2H), 7.11-6.87 (dd, J = 7.8, 2.7 Hz, 1H), 4.47-4.29 (s, 1H), 3.72-3.47 (s, 2H), 1.27-1.08 (m, 2H), 1.08-0.86 (s, 2H). 393 97% 3-74

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.85-14.61 (s, 1H), 10.68-10.51 (s, 1H), 9.04-8.78 (m, 1H), 8.01-7.81 (m, 1H), 7.38-7.11 (m, 2H), 7.11-6.87 (dd, J = 7.8, 2.7 Hz, 1H), 4.47-4.29 (s, 1H), 3.72-3.47 (s, 2H), 2.66-2.57 (d, J = 2.7 Hz, 3H), 2.55-2.45 (d, J = 3.4 Hz, 4H). 424 97% 3-75

OMe Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.80-14.62 (m, 1H), 8.38-8.18 (m, 1H), 8.03-7.83 (m, 1H), 8.96-8.82 (m, 1H), 7.77-7.59 (m, 1H), 7.37-7.22 (m, 1H), 4.48-4.29 (m, 1H), 3.24-3.08 (m, 2H), 3.94-3.70 (m, 2H), 1.32-1.12 (m, 2H), 1.12-0.86 (m, 2H). 394 100% 3-76

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 15.11-14.26 (d, J = 53.0 Hz, 1H), 10.22-9.45 (m, 1H), 9.01-8.84 (m, 1H), 8.77-8.58 (s, 1H), 8.09-7.92 (d, J = 8.5 Hz, 1H), 7.88- 7.68 (s, 1H), 7.51-7.33 (s, 1H), 4.84-4.58 (s, 2H), 4.53-4.25 (s, 1H), 2.96- 2.72 (s, 6H), 2.72-2.56 (s, 3H), 1.34-1.17 (d, J = 6.5 Hz, 2H), 1.17-0.93 (d, J = 10.1 Hz, 2H). 435 94% 3-77

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.87-14.59 (s, 1H), 12.20-12.00 (s, 1H), 9.01-8.79 (s, 1H), 8.09-7.83 (d, J = 8.6 Hz, 1H), 7.74-7.59 (s, 1H), 7.39-7.20 (m, 2H), 4.48-4.31 (s, 1H), 2.72-2.56 (s, 3H), 1.36-1.12 (d, J = 6.9 Hz, 2H), 1.12-0.79 (s, 2H). 411 98% 3-78

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.85-14.61 (s, 1H, 10.68-10.51 (s, 1H), 9.04-8.78 (m, 1H), 8.01-7.81 (m, 1H), 7.36-7.11 (m, 2H), 7.11-6.87 (dd, J = 7.8, 2.7 Hz, 1H), 4.47-4.29 (s, 1H), 3.72-3.47 (s, 2H), 1.27-1.08 (m, 2H), 1.08-0.86 (s, 2H). 393 95% 3-79

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.82-14.60 (s, 1H), 11.50-11.28 (s, 1H), 8.99-8.81 (s, 1H), 8.09-7.90 (m, 2H), 7.66-7.53 (d, J = 1.1 Hz, 1H), 6.91-6.78 (s, 1H), 6.17-5.99 (d, J = 15.7 Hz, 1H), 5.38-5.23 (d, J = 9.0 Hz, 1H), 4.48- 4.31 (dd, J = 8.4, 4.4 Hz, 1H), 3.61-3.41 (s, 1H), 2.71-2.56 (s, 3H), 1.32-1.16 (s, 2H), 1.14-0.97 (s, 2H). 421 97% 3-80

MeO Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.82-14.60 (s, 1H), 11.50-11.28 (s, 1H), 8.99-8.81 (s, 1H), 8.09-7.90 (m, 2H), 7.66-7.53 (d, J = 1.1 Hz, 1H), 6.91-6.78 (s, 1H), 6.17-5.99 (d, J = 15.7 Hz, 1H), 5.38-5.23 (d, J = 9.0 Hz, 1H), 4.48-4.31 (dd, J = 8.4, 4.4 Hz, 1H), 3.61-3.41 (s, 1H), 2.71-2.56 (s, 3H), 1.14-0.97 (s, 4H). 437 90% 3-81

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.85-14.61 (s, 1H), 10.95-10.69 (s, 1H), 9.06-8.79 (s, 2H), 8.05-7.90 (d, J = 8.7 Hz, 1H), 7.28-7.09 (s, 1H), 6.85-6.63 (s, 1H), 4.46-4.29 (tt, J = 7.4, 4.0 Hz, 1H), 2.72-2.54 (s, 3H), 1.32-1.14 (d, J = 5.8 Hz, 2H), 1.14-0.97 (d, J = 3.8 Hz, 2H). 394 94% 3-82

OMe Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.89-14.50 (s, 2H), 11.09-10.63 (s, 1H), 9.21-8.97 (s, 1H), 8.97-8.73 (s, 1H), 8.07-7.85 (m, 1H), 3.48-3.31 (m, 5H), 7.42-7.26 (m, 1H), 7.04-6.87 (m, 1H), 4.31-4.13 (p, J = 5.6 Hz, 1H), 2.72-2.54 (s, 3H), 1.27-1.01 (d, J = 5.6 Hz, 4H). 410 98% 3-83

OMe Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 15.05-14.39 (s, 1H), 13.02-12.32 (s, 1H), 8.97-8.77 (s, 1H), 8.47-8.20 (s, 1H), 7.85-7.39 (m, 2H), 7.33-6.98 (d, J = 8.0 Hz, 1H), 4.47-4.23 (s, 1H), 2.74-2.52 (s, 3H), 1.34-1.13 (m, 2H), 1.13-0.71 (s, 2H). 428 100% 3-84

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.75 (d, J = 8.7 Hz, 1H), 8.91 (s, 1H), 8.13 (s, 1H), 7.99 (t, J = 11.1 Hz, 1H), 7.78 (t, J = 13.2 Hz, 1H), 7.72 (s, 1H), 7.33 (d, J = 8.5 Hz, 1H), 7.07 (s, 1H), 4.40 (m, 1H), 2.61 (s, 3H), 1.24 (d, J = 5.7 Hz, 2H), 1.08 (s, 2H). 378 98% 3-85

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.70 (s, 1H), 8.90 (s, 1H), 8.21 (d, J = 8.0 Hz, 1H), 7.98 (d, J = 8.1 Hz, 1H), 7.94 (s, 1H), 7.90 (s, 1H), 7.56 (s, 1H), 7.38 (d, J = 7.9 Hz, 1H), 4.38 (s, 1H), 2.65 (s, 3H), 1.17 (m, 2H), 1.06 (m, 2H). 394 98% 3-86

¹H NMR (400 MHz, DMSO) δ 15.38-14.22 (s, 1H), 9.14-9.08 (s, 1H), 9.00-8.94 (s, 1H), 8.32-8.24 (s, 1H), 7.93-7.90 (s, 1H), 7.90-7.86 (s, 1H), 7.83-7.76 (d, J = 9.72 Hz, 1H), 5.07-4.96 (d, J = 6.74 Hz, 1H), 4.65-4.56 (d, J = 11.26 Hz, 1H), 4.53-4.43 (d, J = 9.86 Hz, 1H), 1.54-1.46 (d, J = 6.76 Hz, 3H). 414 99% 3-87

¹H NMR (400 MHz, DMSO) δ 14.87 (s, 1H), 8.93 (s, 1H), 8.77 (s, 1H), 8.27 (d, J = 8.2 Hz, 1H), 8.15 (s, 1H), 7.73 (d, J = 0.9 Hz, 1H), 7.63 (m, 2H), 4.46-4.36 (m, 1H), 2.76 (s, 3H), 1.29 (d, J = 6.5 Hz, 2H), 1.08 (t, J = 7.4 Hz, 2H). 394 99%

TABLE 4

Com- pound MS No. R³ = NMR (MH⁺) HPLC 4-1

¹H NMR (400 MHz, DMSO) δ 14.49 (s, 1H), 11.38 (s, 1H), 8.70 (s, 1H), 7.78 (d, J = 9.1 Hz, 1H), 7.42 (d, J = 7.9 Hz, 1H), 7.26 (d, J = 8.1 Hz, 1H), 7.00-6.92 (m, 1H), 6.86 (t, J = 7.5 Hz, 1H), 6.51 (s, 1H), 4.24-4.16 (m, 1H), 2.56 (s, 3H), 1.03 (dd, J = 12.0, 4.6 Hz, 2H), 0.86 (d, J = 7.4 Hz, 2H). 377 95% 4-2

¹H NMR (400 MHz, DMSO) δ 14.70 (s, 1H), 11.59 (s, 1H), 8.92 (s, 1H), 8.00 (d, J = 9.1 Hz, 1H), 7.64 (d, J = 7.5 Hz, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.19 (t, J = 7.5 Hz, 1H), 7.08 (t, J = 7.3 Hz, 1H), 6.73 (s, 1H), 4.42 (s, 1H), 2.78 (s, 3H), 1.27 (d, J = 6.1 Hz, 2H), 1.07 (s, 2H). 377 100% 4-3

¹H NMR (400 MHz, DMSO) δ 14.66 (s, 1H), 8.93 (s, 1H), 8.05 (d, J = 8.6 Hz, 1H), 7.65 (d, J = 7.7 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.30-7.24 (m, 1H), 7.14 (t, J = 7.3 Hz, 1H), 6.68 (s, 1H), 4.41 (s, 1H), 3.58 (s, 3H), 2.65 (s, 3H), 1.24 (s, 4H). 391 98% 4-4

¹H NMR (400 MHz, DMSO) δ 14.82 (s, 1H), 11.36 (s, 1H), 8.90 (s, 1H), 7.95 (d, J = 7.8 Hz, 1H), 7.57 (s, 3H), 7.46 (s, 1H), 7.07 (d, J = 8.5 Hz, 1H), 6.53 (s, 1H), 4.39 (s, 1H), 2.62 (s, 3H), 1.24 (s, 2H), 1.09 (d, J = 18.8 Hz, 2H). 377 87% 4-5

¹H NMR (400 MHz, DMSO) δ 14.71 (s, 1H), 11.55 (s, 1H), 8.92 (s, 1H), 8.00 (d, J = 9.0 Hz, 1H), 7.30 (d, J = 8.4 Hz, 1H), 7.09 (t, J = 7.4 Hz, 1H), 6.87 (d, J = 6.9 Hz, 1H), 6.75 (s, 1H), 4.42 (s, 1H), 2.79 (s, 3H), 2.09 (s, 3H), 1.28 (d, J = 6.0 Hz, 2H), 1.07 (s, 2H). 391 90% 4-6

¹H NMR (400 MHz, DMSO) δ 14.71 (s, 1H), 11.43 (s, 1H), 8.91 (s, 1H), 7.99 (d, J = 8.7 Hz, 1H), 7.37 (d, J = 8.6 Hz, 1H), 7.13 (s, 1H), 6.84 (d, J = 8.7 Hz, 1H), 6.63 (s, 1H), 4.41 (s, 1H), 3.78 (s, 4H), 2.77 (s, 3H), 1.26 (d, J = 5.7 Hz, 2H), 1.07 (s, 2H). 407 92.3% 4-9

¹H NMR (400 MHz, DMSO) δ 14.65 (s, 1H), 12.23 (d, J = 30.1 Hz, 1H), 8.93 (s, 1H), 8.20 (d, J = 11.8 Hz, 1H), 7.65 (s, 1H), 7.53 (s, 2H), 6.87 (d, J = 26.1 Hz, 1H), 4.38 (d, J = 31.7 Hz, 1H), 2.74 (d, J = 19.6 Hz, 3H), 1.24 (d, J = 8.9 Hz, 2H), 1.07 (s, 2H). 402 92.8% 4-10

¹H NMR (400 MHz, DMSO) δ 14.67 (s, 1H), 11.70 (s, 1H), 8.92 (s, 1H), 8.00 (d, J = 8.9 Hz, 1H), 7.52-7.44 (m, 1H), 7.41 (d, J = 9.8 Hz, 1H), 7.04 (t, J = 9.3 Hz, 1H), 6.72 (s, 1H), 4.42 (s, 1H), 2.77 (s, 3H), 1.26 (d, J = 6.4 Hz, 2H), 1.07 (s, 2H). 395 89.7% 4-11

¹H NMR (400 MHz, DMSO) δ 14.68 (s, 1H), 11.98 (s, 1H), 8.93 (s, 1H), 8.02 (d, J = 9.1 Hz, 1H), 7.47 (d, J = 7.3 Hz, 1H), 7.19 (q, J = 7.8 Hz, 2H), 6.76 (s, 1H), 4.42 (s, 1H), 2.78 (s, 3H), 1.27 (d, J = 6.2 Hz, 2H), 1.08 (s, 2H). 411 97% 4-12

¹H NMR (400 MHz, DMSO) δ 14.64 (s, 1H), 12.30 (s, 1H), 8.93 (s, 1H), 8.04 (d, J = 8.3 Hz, 1H), 7.86 (d, J = 6.8 Hz, 1H), 7.64 (s, 1H), 7.36 (s, 1H), 6.91 (s, 1H), 4.43 (s, 1H), 2.78 (s, 3H), 1.28 (s, 2H), 1.09 (s, 2H). 402 99% 4-13

¹H NMR (400 MHz, DMSO) δ 14.66 (s, 1H), 11.93 (s, 1H), 8.92 (s, 1H), 8.01 (d, J = 9.1 Hz, 1H), 7.33 (d, J = 8.3 Hz, 1H), 7.17 (d, J = 6.5 Hz, 1H), 6.87 (t, J = 8.9 Hz, 1H), 6.80 (s, 1H), 4.42 (s, 1H), 2.78 (s, 3H), 1.27 (d, J = 6.4 Hz, 2H), 1.07 (s, 2H). 395 87% 4-14

¹H NMR (400 MHz, DMSO) δ 14.70 (s, 1H), 11.43 (s, 1H), 8.92 (s, 1H), 8.00 (d, J = 8.8 Hz, 1H), 7.46 (s, 1H), 6.98 (s, 2H), 6.67 (s, 1H), 4.42 (s, 1H), 2.77 (s, 3H), 1.26 (d, J = 6.3 Hz, 2H), 1.09 (s, 2H). 391 92.7% 4-15

¹H NMR (400 MHz, DMSO) δ 11.07 (s, 1H), 9.02 (s, 1H), 8.04 (s, 1H), 7.55 (s, 2H), 7.29 (s, 1H), 6.96 (s, 1H), 6.67 (s, 1H), 2.85 (s, 3H), 2.47 (s, 3H), 1.34 (s, 2H), 1.09 (s, 2H). 391 99% 4-16

¹H NMR (400 MHz, DMSO) δ 14.64 (s, 1H), 12.41 (s, 1H), 8.93 (s, 1H), 8.69 (s, 1H), 8.07 (d, J = 13.8 Hz, 2H), 7.67 (s, 1H), 7.05 (s, 1H), 4.42 (s, 1H), 2.78 (s, 3H), 1.26 (s, 2H), 1.08 (s, 2H). 422 100% 4-17

¹H NMR (400 MHz, DMSO) δ 14.70 (s, 1H), 11.70 (s, 1H), 8.92 (s, 1H), 8.00 (d, J = 9.0 Hz, 1H), 7.65 (s, 1H), 7.24 (d, J = 10.1 Hz, 1H), 6.96 (t, J = 9.1 Hz, 1H), 6.76 (s, 1H), 4.42 (s, 1H), 2.77 (s, 3H), 1.26 (d, J = 5.7 Hz, 2H), 1.07 (s, 2H). 395 88% 4-18

¹H NMR (400 MHz, DMSO) δ 14.68 (s, 1H), 12.08 (s, 1H), 8.92 (s, 1H), 8.01 (d, J = 8.9 Hz, 1H), 7.47 (d, J = 6.4 Hz, 1H), 7.04 (d, J = 9.3 Hz, 2H), 6.79 (s, 1H), 4.42 (s, 1H), 2.76 (s, 3H), 1.26 (d, J = 6.2 Hz, 2H), 1.08 (s, 2H). 395 89.1% 4-19

¹H NMR (400 MHz, DMSO) δ 14.65 (s, 1H), 12.66 (s, 1H), 11.98 (s, 1H), 8.93 (s, 1H), 8.12 (s, 1H), 8.03 (d, J = 8.8 Hz, 1H), 7.70 (q, J = 8.2 Hz, 2H), 6.83 (s, 1H), 4.43 (s, 1H), 2.78 (s, 3H), 1.27 (d, J = 6.2 Hz, 2H), 1.08 (s, 2H). 421 100% 4-20

¹H NMR (400 MHz, DMSO) δ 14.68 (s, 1H), 11.78 (s, 1H), 8.92 (s, 1H), 8.01 (d, J = 9.0 Hz, 1H), 7.66 (d, J = 8.6 Hz, 1H), 7.51 (s, 1H), 7.10 (d, J = 8.4 Hz, 1H), 6.77 (s, 1H), 4.42 (s, 1H), 2.77 (s, 3H), 1.26 (d, J = 6.1 Hz, 2H), 1.07 (s, 2H). 411 90% 4-21

¹H NMR (400 MHz, DMSO) δ 14.49 (s, 1H), 12.71 (s, 1H), 8.92 (s, 1H), 8.15 (s, 1H), 8.04 (d, J = 9.4 Hz, 2H), 7.43 (s, 1H), 7.29 (s, 1H), 4.42 (s, 1H), 2.79 (s, 3H), 1.27 (s, 2H), 1.08 (s, 2H). 422 97% 4-22

¹H NMR (400 MHz, MeOD) δ 8.96 (s, 1H), 7.93 (d, J = 9.1 Hz, 1H), 7.55 (d, J = 12.6 Hz, 2H), 7.47 (s, 1H), 7.34 (d, J = 8.1 Hz, 1H), 6.77 (s, 1H), 6.57 (d, J = 7.9 Hz, 1H), 6.51 (s, 1H), 4.29 (s, 1H), 2.78 (s, 3H), 1.38-1.24 (m, 2H), 1.20 (s, 2H). 393 90% 4-23

¹H NMR (400 MHz, DMSO) δ 14.68 (s, 1H), 11.82 (s, 1H), 8.92 (s, 1H), 8.01 (d, J = 8.5 Hz, 1H), 7.70 (s, 1H), 7.50 (d, J = 8.3 Hz, 1H), 7.19 (d, J = 9.4 Hz, 1H), 6.73 (s, 1H), 4.42 (s, 1H), 2.76 (s, 3H), 1.26 (d, J = 6.1 Hz, 2H), 1.07 (s, 2H). 411 90% 4-24

¹H NMR (400 MHz, DMSO) δ 14.63 (s, 1H), 11.61 (s, 1H), 8.95 (d, J = 9.5 Hz, 1H), 8.41 (s, 1H), 7.99 (s, 1H), 7.67 (d, J = 9.1 Hz, 1H), 6.52 (s, 1H), 4.43 (s, 1H), 2.78 (s, 3H), 1.25 (s, 2H), 1.08 (s, 2H). 422 90% 4-25

¹H NMR (400 MHz, DMSO) δ 14.82 (s, 1H), 11.31 (s, 1H), 8.91 (s, 1H), 7.97 (d, J = 8.4 Hz, 1H), 7.71 (d, J = 7.8 Hz, 1H), 7.48 (s, 1H), 7.41 (s, 1H), 6.99 (d, J = 7.9 Hz, 1H), 6.53 (s, 1H), 4.40 (s, 1H), 2.63 (s, 3H), 1.24 (s, 2H), 1.08 (s, 2H). 377 100% 4-26

¹H NMR (400 MHz, DMSO) δ 14.70 (s, 1H), 12.37 (s, 1H), 8.93 (s, 1H), 8.19 (t, J = 9.0 Hz, 2H), 8.01 (d, J = 8.0 Hz, 1H), 7.34 (s, 1H), 7.00 (s, 1H), 4.43 (s, 1H), 2.75 (s, 3H), 1.24 (s, 2H), 1.11 (s, 2H). 422 99% 4-27

¹H NMR (400 MHz, DMSO) δ 14.73 (s, 1H), 11.45 (s, 1H), 9.17 (s, 1H), 8.92 (s, 1H), 7.99 (d, J = 8.6 Hz, 1H), 7.77 (s, 1H), 7.35 (d, J = 8.5 Hz, 1H), 7.24 (s, 1H), 6.64 (s, 1H), 4.42 (s, 1H), 2.77 (s, 2H), 1.46 (d, J = 29.9 Hz, 9H), 1.25 (s, 2H), 1.06 (s, 2H). 492 100% 4-28

¹H NMR (400 MHz, DMSO) δ 14.67 (s, 1H), 11.94 (s, 1H), 9.97 (s, 2H), 8.93 (s, 1H), 8.02 (d, J = 8.7 Hz, 1H), 7.65 (s, 1H), 7.60 (d, J = 8.6 Hz, 1H), 7.19-7.13 (m, 1H), 6.84 (s, 1H), 4.42 (s, 2H), 2.76 (s, 3H), 1.14-1.00 (m, 4H). 392 94% 4-29

¹H NMR (400 MHz, DMSO) δ 14.67 (s, 1H), 11.94 (s, 1H), 9.97 (s, 2H), 8.93 (s, 1H), 8.02 (d, J = 8.7 Hz, 1H), 7.65 (s, 1H), 7.60 (d, J = 8.6 Hz, 1H), 7.19-7.13 (m, 1H), 6.84 (s, 1H), 4.42 (s, 2H), 2.76 (s, 3H), 1.14-1.00 (m, 4H). 391 100% 4-30

¹H NMR (400 MHz, DMSO) δ 14.73 (s, 1H), 11.38 (s, 1H), 9.33 (s, 1H), 8.91 (s, 1H), 7.98 (d, J = 9.1 Hz, 1H), 7.81 (s, 1H), 7.48 (d, J = 8.3 Hz, 1H), 7.09 (d, J = 8.7 Hz, 1H), 6.64 (s, 1H), 4.42 (s, 1H), 2.78 (s, 3H), 1.51 (s, 10H), 1.25 (d, J = 8.9 Hz, 2H), 1.08 (dd, J = 14.0, 6.3 Hz, 2H). 492 97% 4-31

H NMR (400 MHz, DMSO) δ 14.31 (s, 1H), 11.68 (s, 1H), 8.94 (s, 1H), 8.17 (d, J = 8.7 Hz, 1H), 7.66 (d, J = 7.8 Hz, 1H), 7.49 (d, J = 8.1 Hz, 1H), 7.21 (t, J = 7.5 Hz, 1H), 7.08 (t, J = 7.4 Hz, 1H), 6.80 (s, 1H), 4.44 (s, 1H), 1.25 (d, J = 6.4 Hz, 2H), 1.12 (s, 2H). 397 100% 4-32

¹H NMR (400 MHz, DMSO) δ 14.72 (s, 1H), 11.74 (s, 1H), 9.35 (s, 2H), 8.92 (s, 1H), 8.00 (d, J = 9.0 Hz, 1H), 7.66 (d, J = 8.5 Hz, 1H), 7.34 (s, 1H), 6.94 (d, J = 8.3 Hz, 1H), 6.76 (s, 1H), 4.42 (s, 1H), 2.78 (s, 3H), 1.27 (d, J = 5.6 Hz, 3H), 1.06 (s, 2H). 392 97% 4-33

¹H NMR (400 MHz, DMSO) δ 14.73 (s, 1H), 11.56 (s, 1H), 9.17 (s, 1H), 8.93 (s, 1H), 8.00 (d, J = 7.7 Hz, 1H), 7.46 (s, 2H), 7.12 (d, J = 20.9 Hz, 2H), 5.18-4.56 (m, 1H), 4.44 (s, 1H), 2.80 (s, 3H), 1.24 (s, 2H), 1.07 (s, 2H). 492 91% 4-34

¹H NMR (400 MHz, DMSO) δ 14.70 (s, 1H), 11.77 (s, 1H), 8.93 (s, 1H), 8.01 (d, J = 8.4 Hz, 1H), 7.23-7.03 (m, 2H), 6.88 (s, 1H), 6.76 (d, J = 6.4 Hz, 1H), 4.43 (m, 1H), 2.77 (s, 3H), 1.24 (d, J = 6.6 Hz, 2H), 1.12 (s, 2H). 392 99% 4-35

¹H NMR (400 MHz, DMSO) δ 14.28 (s, 1H), 11.79 (s, 1H), 8.94 (s, 1H), 8.17 (d, J = 8.8 Hz, 1H), 7.56-7.38 (m, 2H), 7.06 (t, J = 8.8 Hz, 1H), 6.79 (s, 1H), 4.44 (s, 1H), 1.24 (d, J = 6.6 Hz, 1H), 1.12 (s, 2H). 415 91% 4-36

¹H NMR (400 MHz, DMSO) δ 14.28 (s, 1H), 12.16 (s, 1H), 8.95 (s, 1H), 8.18 (d, J = 8.0 Hz, 1H), 7.49 (d, J = 4.2 Hz, 1H), 7.05 (d, J = 8.5 Hz, 2H), 6.85 (s, 1H), 4.43 (s, 1H), 1.24 (s, 2H), 1.13 (s, 2H). 415 95% 4-37

¹H NMR (400 MHz, DMSO) δ 14.26 (s, 1H), 12.07 (s, 1H), 8.95 (s, 1H), 8.19 (d, J = 8.5 Hz, 1H), 7.49 (d, J = 7.6 Hz, 1H), 7.29-7.07 (m, 2H), 6.81 (s, 1H), 4.44 (s, 1H), 1.25 (s, 2H), 1.13 (s, 2H). 431 95% 4-38

¹H NMR (400 MHz, DMSO) δ 14.28 (s, 1H), 12.04 (s, 1H), 8.95 (s, 1H), 8.19 (d, J = 8.7 Hz, 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.20 (s, 1H), 6.93-6.81 (m, 2H), 4.44 (s, 1H), 1.24 (s, 2H), 1.13 (s, 2H). 415 87% 4-39

¹H NMR (400 MHz, DMSO) δ 14.71 (s, 1H), 11.66 (s, 1H), 10.06 (s, 1H), 8.92 (s, 1H), 8.02 (s, 3H), 7.46 (s, 1H), 7.31 (s, 1H), 7.19 (s, 1H), 7.06 (s, 1H), 6.90 (s, 1H), 4.42 (s, 1H), 3.85 (s, 3H), 2.79 (s, 3H), 1.26 (s, 2H), 1.07 (s, 2H). 526 95.6% 4-40

¹H NMR (400 MHz, DMSO) δ 14.71 (s, 1H), 11.62 (s, 1H), 10.05 (s, 1H), 8.93 (s, 1H), 7.99 (d, J = 9.2 Hz, 1H), 7.70 (d, J = 7.5 Hz, 2H), 7.28-6.87 (m, 6H), 4.42 (s, 1H), 3.75 (s, 3H), 2.68 (s, 3H), 1.25 (d, J = 9.3 Hz, 2H), 1.05 (d, J = 18.8 Hz, 2H). 562 96% 4-41

¹H NMR (400 MHz, DMSO) δ 14.73 (s, 1H), 11.66 (s, 1H), 9.62 (s, 1H), 8.93 (s, 1H), 8.02 (d, J = 8.7 Hz, 1H), 7.72 (s, 1H), 7.21 (s, 1H), 7.12 (s, 1H), 7.04 (s, 1H), 4.44 (s, 1H), 3.05 (s, 1H), 2.82 (d, J = 25.3 Hz, 3H), 1.12 (d, J = 24.4 Hz, 10H). 462 87% 4-42

¹H NMR (400 MHz, DMSO) δ 11.87 (s, 1H), 9.18 (s, 1H), 8.08-7.63 (m, 2H), 7.48 (s, 2H), 7.20 (s, 2H), 6.95 (s, 2H), 4.54 (s, 1H), 4.24 (s, 2H), 2.81 (s, 3H), 1.29 (s, 2H), 1.06 (s, 2H). 406 97% 4-43

¹H NMR (400 MHz, DMSO) δ 14.78 (s, 1H), 11.70 (s, 1H), 8.98 (s, 1H), 8.06 (d, J = 9.0 Hz, 1H), 7.49 (s, 1H), 7.43 (d, J = 7.4 Hz, 1H), 7.20 (s, 1H), 7.00 (d, J = 6.8 Hz, 1H), 6.91 (s, 1H), 4.49 (s, 3H), 2.84 (s, 3H), 1.46 (s, 9H), 1.30 (s, 2H), 1.13 (s, 2H). 506 98% 4-44

¹H NMR (400 MHz, DMSO) δ 14.76 (s, 1H), 12.92 (s, 1H), 8.92 (s, 1H), 8.79 (s, 1H), 8.07 (s, 1H), 7.99 (d, J = 8.6 Hz, 1H), 7.77 (d, J = 8.3 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H), 4.40 (s, 1H), 2.62 (s, 3H), 1.25 (d, J = 5.7 Hz, 2H), 1.10 (s, 2H). 422 100% 4-45

¹H NMR (400 MHz, DMSO) δ 11.65 (s, 1H), 9.57 (s, 1H), 8.82 (s, 1H), 7.93 (d, J = 8.3 Hz, 1H), 7.71 (d, J = 5.5 Hz, 1H), 7.19 (s, 1H), 7.09 (s, 1H), 7.00 (s, 1H), 4.32 (s, 1H), 2.72 (d, J = 18.9 Hz, 3H), 1.89-1.77 (m, 5H), 1.65 (s, 1H), 1.45 (d, J = 10.5 Hz, 2H), 1.35-1.16 (m, 6H), 0.97 (s, 2H). 502 89% 4-46

¹H NMR (400 MHz, DMSO) δ 14.69 (s, 1H), 11.94 (s, 1H), 9.39 (s, 1H), 8.92 (s, 1H), 8.00 (d, J = 7.8 Hz, 1H), 7.72 (s, 1H), 7.28 (s, 1H), 7.15 (s, 1H), 6.81 (s, 1H), 4.43 (s, 1H), 4.27-4.13 (m, 2H), 2.79 (s, 3H), 2.33 (s, 1H), 2.17 (s, 1H), 1.59 (d, J = 14.2 Hz, 2H), 1.26 (s, 5H), 1.07 (s, 2H), 0.85 (dd, J = 54.3, 14.6 Hz, 14H). 588 86.3% 4-47

¹H NMR (400 MHz, DMSO) δ 14.73 (s, 1H), 11.74 (s, 1H), 10.60 (s, 1H), 9.30 (s, 1H), 8.92 (s, 1H), 8.61 (d, J = 7.6 Hz, 1H), 8.11 (d, J = 7.9 Hz, 1H), 8.01 (d, J = 8.8 Hz, 1H), 7.59 (d, J = 6.7 Hz, 1H), 7.37 (d, J = 7.8 Hz, 1H), 7.24 (d, J = 8.0 Hz, 1H), 6.97 (s, 1H), 4.43 (s, 1H), 2.79 (s, 3H), 1.25 (s, 2H), 1.07 (s, 2H). 565 96% 4-48

¹H NMR (400 MHz, DMSO) δ 14.70 (s, 1H), 11.74 (s, 1H), 9.76 (s, 1H), 8.93 (s, 1H), 8.01 (d, J = 8.7 Hz, 1H), 7.29 (d, J = 6.6 Hz, 1H), 7.23-7.01 (m, 3H), 4.43 (s, 1H), 3.49 (d, J = 14.6 Hz, 1H), 3.06 (d, J = 14.8 Hz, 1H), 2.37 (dd, J = 27.4, 15.5 Hz, 2H), 2.04 (s, 1H), 1.91 (d, J = 17.7 Hz, 2H), 1.51 (d, J = 11.3 Hz, 1H), 1.41 (d, J = 10.3 Hz, 1H), 1.25 (s, 2H), 1.09 (d, J = 11.8 Hz, 3H), 0.98 (s, 2H), 0.77 (d, J = 22.2 Hz, 3H). 606 88% 4-49

¹H NMR (400 MHz, DMSO) δ 14.69 (s, 1H), 11.58 (s, 1H), 10.29 (s, 1H), 8.91 (s, 1H), 8.40 (s, 1H), 8.05 (dd, J = 15.6, 8.6 Hz, 2H), 7.97 (s, 2H), 7.83 (d, J = 8.2 Hz, 1H), 7.72-7.56 (m, 2H), 7.18 (d, J = 8.0 Hz, 1H), 7.04 (t, J = 8.0 Hz, 1H), 6.98 (d, J = 7.5 Hz, 1H), 6.81 (s, 1H), 4.35 (s, 1H), 2.54 (s, 3H), 1.23 (s, 2H), 1.04 (s, 2H). 582 100% 4-50

¹H NMR (400 MHz, DMSO) δ 14.72 (s, 1H), 11.68 (s, 1H), 10.26 (s, 1H), 8.92 (s, 1H), 8.00 (s, 1H), 7.74 (s, 1H), 7.29 (s, 1H), 7.19 (s, 1H), 7.03 (s, 1H), 6.93 (s, 2H), 4.43 (s, 1H), 2.79 (s, 3H), 2.31 (s, 6H), 2.10 (s, 3H), 1.24 (s, 2H), 1.07 (s, 2H). 538 90% 4-51

¹H NMR (400 MHz, DMSO) δ 14.73 (s, 1H), 11.62 (s, 1H), 10.08 (s, 1H), 8.93 (s, 1H), 8.00 (d, J = 7.6 Hz, 1H), 7.76 (d, J = 8.6 Hz, 2H), 7.18 (d, J = 7.7 Hz, 2H), 7.02 (d, J = 18.7 Hz, 2H), 4.44 (s, 1H), 3.63 (s, 3H), 2.76 (s, 3H), 1.24 (s, 2H), 1.08 (s, 2H). 536 99% 4-52

¹H NMR (400 MHz, DMSO) δ 14.72 (s, 1H), 11.68 (s, 1H), 9.29 (s, 1H), 8.93 (s, 1H), 8.81 (s, 1H), 8.31 (s, 1H), 8.03 (d, J = 8.9 Hz, 1H), 7.15 (s, 2H), 7.02 (dd, J = 24.0, 8.3 Hz, 2H), 6.94 (s, 1H), 4.44 (s, 1H), 3.91 (s, 3H), 2.80 (s, 3H), 1.25 (d, J = 15.5 Hz, 2H), 1.08 (s, 2H). 575 96% 4-53

¹H NMR (400 MHz, DMSO) δ 14.71 (s, 1H), 11.72 (s, 1H), 10.04 (s, 1H), 8.94 (s, 1H), 8.02 (d, J = 10.3 Hz, 1H), 7.71 (d, J = 7.0 Hz, 1H), 7.24 (s, 1H), 7.15 (d, J = 7.3 Hz, 1H), 7.04 (s, 1H), 4.44 (s, 1H), 3.98 (s, 2H), 3.76 (s, 2H), 3.43 (s, 2H), 3.07 (d, J = 24.3 Hz, 4H), 2.78 (s, 3H), 2.69 d, J = 10.9 Hz, 1H), 1.26 (s, 2H), 1.08 (s, 2H). 533 99% 4-54

¹H NMR (400 MHz, DMSO) δ 14.71 (s, 1H), 11.72 (s, 1H), 10.03 (s, 1H), 8.94 (s, 1H), 8.02 (d, J = 8.9 Hz, 1H), 7.70 (s, 1H), 7.24 (s, 1H), 7.14 (s, 1H), 7.03 (s, 1H), 5.33 (s, 1H), 4.43 (s, 1H), 4.03 (s, 2H), 3.03 (s, 4H), 2.78 (s, 3H), 2.00 (d, J = 7.6 Hz, 2H), 1.24 (s, 9H), 1.08 (s, 2H), 0.85 (s, 2H). 632 96% 4-55

¹H NMR (400 MHz, DMSO) δ 14.71 (s, 1H), 11.72 (s, 1H), 10.04 (s, 1H), 9.57 (s, 1H), 8.94 (s, 1H), 8.02 (d, J = 8.9 Hz, 1H), 7.71 (d, J = 7.8 Hz, 1H), 7.26 (d, J = 7.6 Hz, 1H), 7.15 (d, J = 9.1 Hz, 1H), 7.03 (d, J = 9.6 Hz, 1H), 4.44 (s, 1H), 2.99 (s, 1H), 2.82 (s, 3H), 2.78 (s, 2H), 2.54 (s, 2H), 1.26 (s, 2H), 1.08 (s, 2H). 491 91% 4-56

¹H NMR (400 MHz, DMSO) δ 14.71 (s, 1H), 11.87 (s, 1H), 10.45 (s, 1H), 8.93 (s, 1H), 8.02 (d, J = 8.8 Hz, 1H), 7.47 (d, J = 7.2 Hz, 1H), 7.23 (s, 1H), 7.07 (d, J = 7.9 Hz, 1H), 6.68 (s, 1H), 4.42 (s, 1H), 2.78 (s, 3H), 2.68 (s, 3H), 1.26 (s, 2H), 1.08 (s, 2H). 490 96% 4-57

¹H NMR (400 MHz, DMSO) δ 14.78 (s, 1H), 11.75 (s, 1H), 9.64 (s, 1H), 8.92 (s, 1H), 7.99 (d, J = 8.7 Hz, 1H), 7.83 (s, 1H), 7.70 (s, 1H), 7.63 (d, J = 7.8 Hz, 1H), 7.18 (d, J = 8.6 Hz, 1H), 4.48 (s, 2H), 4.40 (s, 1H), 2.72 (d, J = 27.2 Hz, 7H), 2.62 (s, 3H), 1.25 (s, 2H), 1.08 (s, 2H). M-(Me)₂N 389 100% 4-58

¹H NMR (400 MHz, DMSO) δ 14.79 (s, 1H), 9.84 (s, 1H), 8.92 (s, 1H), 7.97 (d, J = 8.2 Hz, 1H), 7.77 (d, J = 8.7 Hz, 1H), 7.62 (s, 1H), 7.56 (s, 1H), 7.20 (d, J = 8.0 Hz, 1H), 6.63 (s, 1H), 4.64 (s, 2H), 4.39 (s, 1H), 3.57 (s, 2H), 2.88 (s, 6H), 2.65 (d, J = 22.8 Hz, 3H), 1.24 (s, 2H), 1.08 (s, 2H). 448 100% 4-59

¹H NMR (400 MHz, DMSO) δ 14.76 (s, 1H), 11.62 (s, 1H), 9.68 (s, 1H), 8.92 (s, 1H), 7.99 (s, 1H), 6.95 (s, 2H), 6.77 (s, 1H), 6.46 (s, 1H), 4.43 (s, 1H), 2.80 (s, 3H), 1.27 (s, 2H), 1.07 (s, 4H). 393 99% 4-60

¹H NMR (400 MHz, DMSO) δ 14.77 (s, 1H), 11.29 (s, 1H), 8.91 (s, 1H), 7.97 (d, J = 9.0 Hz, 1H), 7.13 (s, 1H), 6.97 (s, 1H), 6.61 (s, 1H), 4.42 (s, 1H), 3.80 (d, J = 13.7 Hz, 7H), 2.78 (s, 3H), 1.26 (s, 2H), 1.06 (s, 2H). 437 99% 4-61

¹H NMR (400 MHz, DMSO) δ 14.74 (s, 1H), 11.29 (s, 1H), 8.91 (s, 1H), 8.81 (s, 1H), 7.98 (d, J = 9.1 Hz, 1H), 7.27 (d, J = 8.8 Hz, 1H), 6.93 (s, 1H), 6.71 (d, J = 8.4 Hz, 1H), 6.53 (s, 1H), 4.41 (s, 2H), 2.77 (s, 3H), 1.25 (s, 2H), 1.06 (s, 2H). 393 98% 4-62

¹H NMR (400 MHz, DMSO) δ 14.75 (s, 1H), 11.50 (s, 1H), 9.79 (s, 1H), 8.91 (s, 1H), 7.97 (d, J = 8.7 Hz, 1H), 7.07 (d, J = 6.7 Hz, 1H), 6.86 (s, 1H), 6.60 (s, 2H), 4.41 (s, 1H), 2.76 (s, 3H), 1.23 (s, 2H), 1.08 (s, 2H). 393 100% 4-63

¹H NMR (400 MHz, DMSO) δ 12.18 (s, 1H), 10.24 (s, 1H), 8.93 (s, 1H), 8.04 (d, J = 8.8 Hz, 1H), 7.87 (d, J = 8.8 Hz, 2H), 7.78 (d, J = 7.0 Hz, 1H), 7.46 (d, J = 7.3 Hz, 2H), 7.35 (s, 1H), 4.43 (s, 1H), 2.77 (s, 3H), 1.27 (s, 2H), 1.09 (s, 2H). 405 85% 4-64

¹H NMR (400 MHz, DMSO) δ 14.55 (s, 1H), 13.88 (s, 1H), 8.94 (s, 1H), 8.10 (d, J = 8.4 Hz, 1H), 8.01 (dd, J = 14.5, 7.6 Hz, 2H), 7.62 (s, 1H), 4.44 (s, 1H), 2.71 (s, 3H), 1.24 (s, 2H), 1.08 (s, 2H). 447 89% 4-65

¹H NMR (400 MHz, DMSO) δ 14.44 (s, 1H), 11.53 (s, 1H), 8.84 (s, 1H), 8.16 (d, J = 9.1 Hz, 1H), 7.95 (d, J = 7.2 Hz, 1H), 7.69 (d, J = 9.7 Hz, 1H), 7.58 (t, J = 10.6 Hz, 1H), 7.42 (d, J = 7.4 Hz, 2H), 7.16 (t, J = 7.5 Hz, 1H), 7.04 (t, J = 7.4 Hz, 1H), 6.62 (s, 1H), 5.77 (s, 1H), 1.77 (d, J = 17.9 Hz, 3H). 449 94.06% 4-66

¹H NMR (400 MHz, DMSO) δ 14.79 (s, 1H), 11.42 (s, 1H), 8.70 (s, 1H), 8.04 (d, J = 8.2 Hz, 1H), 7.57 (d, J = 8.2 Hz, 1H), 7.42 (d, J = 8.0 Hz, 1H), 7.25 (s, 1H), 6.96 (d, J = 8.1 Hz, 1H), 6.86 (d, J = 7.7 Hz, 1H), 6.61 (s, 1H), 4.23 (s, 1H), 2.70 (s, 3H), 1.06 (s, 2H), 0.81 (s, 2H). 359 91.2% 4-67

¹H NMR (400 MHz, DMSO) δ 11.76 (s, 1H), 8.71 (s, 1H), 8.16 (d, J = 4.8 Hz, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.36 (s, 1H), 5.94 (dd, J = 3.4, 1.8 Hz, 1H), 5.10 (s, 1H), 4.22-4.08 (m, 1H), 2.33 (s, 3H), 1.09-0.88 (m, 4H). 378 97% 4-68

¹H NMR (400 MHz, DMSO) δ 12.33 (s, 1H), 8.92 (s, 1H), 8.35 (d, J = 4.4 Hz, 1H), 7.99 (d, J = 8.8 Hz, 1H), 7.87 (s, 1H), 7.77 (d, J = 7.8 Hz, 1H), 7.21 (dd, J = 7.7, 4.0 Hz, 1H), 4.47-4.34 (m, 2H), 2.69 (s, 3H), 1.28 (d, J = 6.6 Hz, 2H), 1.10 (s, 2H). 378 98% 4-69

¹H NMR (400 MHz, DMSO) δ 8.94 (s, 1H), 8.39 (t, J = 3.1 Hz, 1H), 8.08 (t, J = 9.0 Hz, 2H), 7.22 (dd, J = 8.1, 4.1 Hz, 1H), 6.74 (d, J = 2.9 Hz, 1H), 4.48-4.36 (m, 1H), 2.67 (s, 3H), 1.26 (d, J = 7.0 Hz, 4H), 1.09 (s, 4H). 392 98% 4-70

¹H NMR (400 MHz, DMSO) δ 8.94 (s, 1H), 8.39 (t, J = 3.1 Hz, 1H), 8.07 (t, J = 9.0 Hz, 1H), 7.21 (dt, J = 7.7, 3.7 Hz, 1H), 6.74 (d, J = 2.9 Hz, 1H), 4.50-4.32 (m, 1H), 2.67 (s, 3H), 1.33-1.19 (d, J = 7.0 Hz, 2H), 1.09 (s, 2H). 392 96% 4-71

¹H NMR (400 MHz, DMSO) δ 14.73 (s, 1H), 11.96 (s, 1H), 8.92 (s, 1H), 8.24 (s, 1H), 8.06 (s, 1H), 8.00 (d, J = 8.7 Hz, 1H), 7.61 (t, J = 2.8 Hz, 1H), 6.57 (s, 1H), 4.59-4.15 (dm, 1H), 2.64 (s, 3H), 1.26 (d, J = 6.8 Hz, 2H), 1.09 (m, 2H). 378 98% 4-72

¹H NMR (400 MHz, DMSO) δ 14.67 (s, 1H), 13.15 (s, 1H), 8.93 (s, 1H), 8.27 (d, J = 6.1 Hz, 1H), 8.01 (d, J = 8.8 Hz, 1H), 7.78 (d, J = 7.9 Hz, 1H), 7.19 (t, J = 7.1 Hz, 1H), 6.88 (s, 1H), 4.49-4.33 (m, 1H), 2.77 (s, 3H), 1.39-1.21 (d, J = 7.0 Hz, 2H), 1.15-1.01 (m, 2H). 394 98% 4-73

¹H NMR (400 MHz, DMSO) δ 14.63 (s, 1H), 12.94 (s, 1H), 8.93 (s, 1H), 8.72 (s, 1H), 8.65 (s, 1H), 8.04 (d, J = 8.7 Hz, 1H), 6.93 (s, 1H), 4.53-4.29 (m, 1H), 2.77 (s, 3H), 1.32-1.19 (m, 3H), 1.17-0.95 (m, 2H). 403 92% 4-74

¹H NMR (400 MHz, DMSO) δ 14.65 (s, 1H), 13.00 (s, 1H), 8.94 (s, 1H), 8.53 (s, 7H), 8.04 (d, J = 8 Hz, 1H), 7.69 (dd, J = 4.4, 2.4 Hz, 1H), 7.01 (s, 6H), 4.58-4.31 (m, 1H), 2.78 (s, 3H), 1.27 (d, J = 6.6 Hz, 15H), 1.18-1.01 (m, 16H). 403 92% 4-75

¹H NMR (400 MHz, DMSO) δ 14.57 (s, 1H), 13.95 (s, 1H), 8.94 (s, 1H), 8.58 (s, 2H), 8.09 (d, J = 8.7 Hz, 1H), 7.60-7.51 (m, 1H), 4.53-4.33 (m, 1H), 2.73 (s, 3H), 1.35-1.17 (m, 2H), 1.15-1.01 (m, 2H). 423 86% 4-76

¹H NMR (400 MHz, DMSO) δ 13.25 (s, 1H), 8.99 (s, 1H), 8.36 (d, J = 5.9 Hz, 1H), 8.07 (d, J = 8.7 Hz, 1H), 7.95 (s, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.28 (t, J = 6.8 Hz, 1H), 4.54-4.44 (m, 1H), 2.76 (s, 3H), 1.34 (d, J = 6.8 Hz, 2H), 1.26-1.06 (m, 2H). 394 98% 4-77

¹H NMR (400 MHz, DMSO) δ 12.56 (s, 1H), 8.93 (s, 1H), 8.38 (t, J = 3.6 Hz, 1H), 8.20 (d, J = 7.4 Hz, 1H), 8.02 (d, J = 9.1 Hz, 1H), 7.26 (dd, J = 8.0, 4.1 Hz, 1H), 6.83 (s, 1H), 4.57-4.33 (m, 1H), 2.78 (s, 3H), 1.35-1.19 (d, J = 6.9 Hz, 2H), 1.15-1.01 (s, 2H). 378 98% 4-78

¹H NMR (400 MHz, DMSO) δ 14.65 (s, 1H), 12.47 (s, 1H), 11.98 (s, 1H), 8.91 (s, 1H), 7.95 (m, 2H), 6.76 (s, 1H), 4.51-4.36 (m, 1H), 2.78 (s, 3H), 1.26 (d, J = 6.9 Hz, 2H), 1.17-1.01 (m, 2H). 395 95% 4-79

¹H NMR (400 MHz, DMSO) δ 14.57 (s, 1H), 13.19 (d, J = 8.5 Hz, 1H), 9.29 (d, J = 2.9 Hz, 1H), 9.02 (d, J = 2.4 Hz, 1H), 8.94 (s, 1H), 8.05 (d, J = 8.8 Hz, 1H), 7.06 (s, 1H), 4.49-4.35 (m, 1H), 2.77 (s, 3H), 1.26 (d, J = 7.2 Hz, 2H), 1.13-0.99 (s, 2H). 379 98% 4-80

¹H NMR (400 MHz, DMSO) δ 15.167 (s, 1H), 14.59 (s, 1H), 13.80 (s, 1H), 9.32 (s, 1H), 8.96 (d, J = 2.3 Hz, 1H), 8.40 (d, J = 6.1 Hz, 1H), 8.25 (d, J = 6.0 Hz, 1H), 8.10 (d, J = 8.4 Hz, 1H), 7.27 (s, 1H), 4.51-4.39 (m, 1H), 2.76 (m, 3H), 1.29-1.17 (d, J = 7.0 Hz, 2H), 1.17-0.97 (m, 2H). 378 85% 4-81

¹H NMR (400 MHz, DMSO) δ 14.56 (s, 1H), 13.05 (s, 1H), 8.95 (s, 1H), 8.68 (s, 1H), 8.08 (d, J = 9.1 Hz, 1H), 7.62 (s, 1H), 7.12 (s, 1H), 4.51-4.36 (m, 1H), 2.76 (s, 3H), 1.33-1.19 (d, J = 7.1 Hz, 2H), 1.13-1.05 (s, 2H). 378 85% 4-82

¹H NMR (400 MHz, DMSO) δ 14.88 (s, 1H), 14.57 (s, 1H), 13.46 (s, 1H), 9.41 (s, 1H), 8.96 (s, 1H), 8.52 (d, J = 6.5 Hz, 1H), 8.21-7.93 (m, 2H), 7.38 (s, 1H), 4.53-4.29 (m, 1H), 2.77 (s, 3H), 1.35- 1.17 (d, J = 6.7 Hz, 2H), 1.19-1.03 (s, 2H). 378 98% 4-83

421 90% 4-84

421 98% 4-85

482 93% 4-86

¹H NMR (400 MHz, DMSO) δ 14.60 (s, 1H), 10.06 (s, 1H), 8.81 (s, 1H), 7.88 (d, J = 8.5 Hz, 1H), 7.21 (s, 1H), 7.05 (d, J = 8.1 Hz, 1H), 6.80 (d, J = 8.1 Hz, 1H), 4.36 (m, 1H), 3.08 (s, 2H), 1.06 (m, 4H). 392 95% 4-87

¹H NMR (400 MHz, DMSO) δ 14.57 (s, 1H), 8.91 (s, 1H), 8.03 (d, J = 9.3 Hz, 1H), 7.80 (d, J = 7.7 Hz, 1H), 7.73 (d, J = 8.3 Hz, 1H), 7.56-7.22 (m, 3H), 4.57-4.32 (m, 1H), 2.84 (s, 3H), 1.27 (m, 2H), 1.06 (m, 2H). 378 98% 4-88

¹H NMR (400 MHz, DMSO) δ 14.50 (s, 1H), 13.22 (s, 1H), 8.84 (s, 1H), 8.10-7.80 (m, 2H), 7.74- 7.58 (s, 1H), 7.49 (s, 1H), 4.38 (m, 1H), 2.78 (s, 3H), 1.30-1.12 (m, 2H), 1.00 (m, 2H). 422 98% 4-89

¹H NMR (400 MHz, DMSO) δ 14.56 (s, 1H), 8.93 (s, 1H), 8.02 (d, J = 9.2 Hz, 1H), 7.76 (dd, J = 8.8, 3.5 Hz, 1H), 7.61 (d, J = 8.6 Hz, 1H), 7.41 (s, 1H), 7.28 (t, J = 9.3 Hz, 1H), 4.43 (m, 1H), 2.82 (s, 3H), 1.26 (d, J = 6.4 Hz, 3H), 1.05 (s, 2H). 396 98% 4-90

¹H NMR (400 MHz, DMSO) δ 8.88 (s, 1H), 7.95 (d, J = 8.9 Hz, 1H), 7.76 (s, 1H), 7.61 (d, J = 8.9 Hz, 1H), 7.36 (s, 1H), 7.20 (t, J = 9.0 Hz, 1H), 4.35 (m, 1H), 2.76 (s, 3H), 1.30-1.09 (m, 3H), 0.96 (s, 2H). 396 98% 4-91

¹H NMR (400 MHz, DMSO) δ 14.57 (s, 1H), 8.86 (s, 1H), 7.96 (m, 3H), 7.59 (s, 1H), 7.41 (d, J = 5.1 Hz, 2H), 4.35 (m, 1H), 2.72 (s, 3H), 1.17 (m, 2H), 1.00 (m, 2H). 394 96% 4-92

¹H NMR (400 MHz, DMSO) δ 14.65 (s, 1H), 8.86 (s, 1H), 8.08 (d, J = 7.6 Hz, 1H), 7.97 (m, 2H), 7.36 (m, 3H), 4.32 (m, 1H), 2.57 (s, 3H), 1.03 (m, 4H). 394 98% 4-93

¹H NMR (400 MHz, DMSO) δ 14.51 (s, 1H), 8.92 (ss, 1H), 8.32 (d, J = 8.1 Hz, 1H), 8.28 (d, J = 8.0 Hz, 1H), 8.05 (t, J = 13.1 Hz, 1H), 7.90 (s, 1H), 7.70 (t, J = 8.2 Hz, 1H), 4.45 (m, 1H), 2.86 (s, 3H), 1.26 (t, J = 11.6 Hz, 2H), 1.10 (d, J = 21.6 Hz, 2H). 423 98% 4-94

¹H NMR (400 MHz, DMSO) δ 14.46 (s, 1H), 8.69 (s, 1H), 8.14 (s, 1H), 7.75 (d, J = 9.2 Hz, 1H), 7.52 (dd, J = 8.8, 3.5 Hz, 1H), 7.20-7.11 (m, 3H), 4.43 (s, 1H), 2.64 (s, 3H), 1.26 (d, J = 6.4 Hz, 3H), 1.05 (s, 2H). 378 98% 4-95

¹H NMR (400 MHz, DMSO) δ 14.55 (s, 1H), 8.94 (s, 1H), 8.05 (d, J = 9.3 Hz, 1H), 7.64 (d, J = 2.9 Hz, 1H), 7.54 (s, 1H), 7.36 (d, J = 6.6 Hz, 2H), 4.44 (m, 1H), 2.85 (s, 3H), 1.34-1.19 (m, 2H), 1.06 (s, 2H). 396 96% 4-96

¹H NMR (400 MHz, DMSO) δ 8.91 (s, 1H), 8.38 (s, 1H), 8.04 (d, J = 9.2 Hz, 1H), 7.96 (d, J = 8.4 Hz, 1H), 7.88 (d, J = 8.5 Hz, 1H), 7.55 (s, 1H), 4.44 (m, 1H), 2.83 (s, 3H), 1.35-1.18 (m, 2H), 1.06 (m, 2H). 403 98% 4-97

¹H NMR (400 MHz, DMSO) δ 14.56 (s, 1H), 8.94 (s, 1H), 8.04 (d, J = 9.1 Hz, 1H), 7.95-7.77 (m, 2H), 7.53-7.33 (m, 2H), 4.45 (m, 1H), 2.83 (s, 3H), 1.27 (d, J = 6.3 Hz, 2H), 1.05 (s, 2H). 462 98% 4-98

¹H NMR (400 MHz, DMSO) δ 14.61 (s, 1H), 8.86 (s, 1H), 7.95 (d, J = 9.0 Hz, 1H), 7.43 (s, 1H), 7.03 (t, J = 8.1 Hz, 1H), 6.77 (d, J = 7.4 Hz, 1H), 6.39 (d, J = 7.1 Hz, 1H), 4.38 (m, 1H), 2.77 (s, 3H), 1.19 (m, 2H), 0.98 (m, 1H). 393 96%

TABLE 5

Com- pound MS No. R³ = R² = R¹ = NMR (MH⁺) HPLC 5-1

Me Cyclopropyl ¹H NMR (400 MHZ, DMSO) δ 14.72 (s, 1H), 10.91 (s, 1H), 8.89 (s, 1H), 7.94 (d, J = 8.60 Hz, 1H), 7.13- 6.90 (m, 3H), 4.67 (s, 2H), 4.38 (s, 1H), 2.62 (s, 3H), 1.23 (d, J = 5.80 Hz, 2H), 1.04 (s, 2H). 409  97% 5-2

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.71 (s, 1H), 10.78 (s, 1H), 8.90 (s, 1H), 7.95 (d, J = 8.72 Hz, 1H), 7.41 (s, 1H), 7.22 (d, J = 8.03 Hz, 1H), 7.13 (d, J = 8.17 Hz, 1H), 4.38 (s, 1H), 3.57 (s, 2H), 2.62 (s, 3H), 1.24 (d, J = 6.14 Hz, 2H), 1.05 (s, 2H). 425  98% 5-3

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.70 (s, 1H), 10.64 (s, 1H), 8.98 (s, 1H), 8.05 (d, J = 8.72 Hz, 1H), 7.90 (s, 1H), 7.62 (s, 1H), 4.92 (s, 2H), 4.46 (s, 1H), 2.71 (s, 3H), 1.30 (s, 3H), 1.15 (s, 2H). 454  97% 5-4

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.66 (s, 1H), 11.39 (s, 1H), 8.90 (s, 1H), 7.96 (d, J = 8.72 Hz, 1H), 7.57 (s, 1H), 7.43 (s, 1H), 4.75 (s, 2H), 4.39 (s, 1H), 2.62 (s, 3H), 1.23 (d, J = 5.26 Hz, 2H), 1.06 (s, 2H). 434  98% 5-5

OMe Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.72 (s, 1H), 10.94 (s, 1H), 8.80 (s, 1H), 7.90 (s, 1H), 7.11 (d, J = 26.18 Hz, 2H), 4.67 (s, 2H), 1.15 (s, 4H). 425  98% 5-6

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.75 (s, 1H), 10.87 (s, 1H), 8.90 (s, 1H), 7.96 (d, J = 8.58 Hz, 1H), 7.14 (d, J = 8.35 Hz, 1H), 6.97 (d, J = 8.15 Hz, 1H), 6.89 (s, 1H), 4.69 (s, 2H), 4.39 (s, 1H), 2.62 (s, 3H), 1.23 (s, 2H), 1.04 (s, 2H). 409  98% 5-9

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.74 (s, 1H), 10.28 (s, 1H), 8.90 (s, 1H), 7.94 (d, J = 8.20 Hz, 1H), 7.23 (s, 1H), 7.17 (s, 1H), 7.03 (s, 1H), 4.38 (s, 2H), 2.97 (s, 2H), 2.63 (s, 2H), 1.23 (s, 2H), 1.04 (s, 2H). 407  85% 5-10

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.71 (s, 1H), 11.47 (s, 1H), 11.39 (s, 1H), 8.91 (s, 1H), 7.98 (d, J = 8.50 Hz, 1H), 7.89 (s, 1H), 7.70 (d, J = 8.10 Hz, 1H), 7.35 (d, J = 8.11 Hz, 1H), 4.40 (s, 1H), 3.49 (d, J = 87.04 Hz, 2H), 2.62 (s, 3H), 1.23 (s, 2H), 1.08 (s, 3H). 422  98% 5-11

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.67 (s, 1H), 11.96 (s, 1H), 11.63 (s, 1H), 8.92 (s, 1H), 8.69 (s, 1H), 8.34 (s, 1H), 8.00 (d, J = 8.65 Hz, 1H), 4.41 (s, 1H), 2.61 (d, J = 29.62 Hz, 3H), 1.24 (d, J = 5.11 Hz, 2H), 1.09 (s, 2H). 423  99% 5-12

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.73 (s. 1H), 12.44- 11.74 (m, 2H), 8.91 (s, 1H), 7.98 (d, J = 8.01 Hz, 1H), 7.53-7.03 (m, 3H), 4.39 (s, 1H), 2.61 (s, 3H), 1.20 (d, J = 26.27 Hz, 3H), 1.05 (s, 2H). 422  96% 5-13

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.83 (s, 1H), 8.88 (s, 1H), 7.90 (s, 2H), 6.70 (s, 3H), 4.27 (d, J = 77.51 Hz, 4H), 2.60 (d, J = 25.07 Hz, 3H), 1.23 (s, 2H), 1.02 (s, 2H). 395  98% 5-14

OMe Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.78 (s, 1H), 8.76 (s, 1H), 7.83 (d, J = 9.18 Hz, 1H), 6.92-6.81 (m, 2H), 6.70 (d, J = 7.26 Hz, 1H), 6.19 (d, J = 22.26 Hz, 1H), 4.16 (s, 4H), 3.39 (s, 3H), 2.50 (s, 7H). 411  96% 5-15

8-N Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.55 (s, 1H), 8.61 (s, 1H), 8.19 (d, J = 11.38 Hz, 1H), 7.55 (d, J = 8.31 Hz, 1H), 7.47 (s, 1H), 6.68 (s, 1H), 6.54 (d, J = 8.26 Hz, 1H), 4.00 (s, 2H), 3.73 (s, 1H), 1.15-0.91 (m, 5H). 382  94% 5-16

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.90 (s, 1H), 8.94 (s, 1H), 7.94 (d, J = 9.06 Hz, 1H), 6.95 (d, J = 8.81 Hz, 2H), 6.63 (d, J = 7.73 Hz, 1H), 6.14 (s, 1H), 4.43 (s, 1H), 3.31 (s, 2H), 2.79 (s, 2H), 2.70 (s, 3H), 1.90 (s, 2H), 1.30 (s, 2H), 1.08 (s, 2H). 393  94% 5-17

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.71 (s, 1H), 8.89 (s, 1H), 8.60 (s, 1H), 7.94 (d, J = 8.81 Hz, 1H), 7.67 (s, 1H), 7.10 (s, 1H), 4.38 (s, 1H), 4.27 (s, 2H), 3.63 (s, 2H), 2.66 (s, 3H), 1.24 (d, J = 5.67 Hz, 2H), 1.07 (s, 2H). 440  97% 5-18

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 10.19 (s, 1H), 8.89 (s, 1H), 7.91 (d, J = 8.74 Hz, 1H), 6.33 (s, 1H), 6.24 (s, 1H), 4.57 (s, 2H), 4.38 (s, 2H), 2.64 (s, 3H), 1.23 (d, J = 5.42 Hz, 3H), 1.03 (s, 2H). 424  97% 5-19

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 8.88 (s, 1H), 7.91 (s, 1H), 6.29 (s, 1H), 6.18 (s, 1H), 4.37 (s, 2H), 4.18 (s, 3H), 3.10 (s, 2H), 2.65 (d, J = 16.81 Hz, 6H), 1.23 (s, 3H), 1.03 (s, 2H). 424  97% 5-20

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 8.97 (s, 1H), 8.01 (d, J = 9.26 Hz, 1H), 7.85-7.65 (m, 2H), 7.64-7.40 (m, 1H), 7.36 (s, 1H), 4.46 (s, 1H), 4.32 (s, 3H), 3.63 (s, 3H), 2.74 (s, 3H), 1.30 (d, J = 5.75 Hz, 2H), 1.11 (s, 2H). 396  98% 5-21

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.72 (s, 1H), 8.85 (d, J = 23.76 Hz, 1H), 7.87 (t, J = 19.93 Hz, 1H), 7.17 (s, 1H), 6.99 (d, J = 9.29 Hz, 2H), 4.37 (s, 1H), 4.20 (s, 2H), 3.59 (s, 1H), 3.44 (s, 2H), 2.63 (s, 3H), 1.24 (s, 2H), 1.07 (d, J = 23.80 Hz, 2H). 420  95% 5-22

OMe Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.67 (s, 1H), 8.78 (s, 1H), 7.87 (d, J = 9.24 Hz, 1H), 7.26 (d, J = 10.63 Hz, 1H), 7.11 (s, 1H), 7.04 (s, 1H), 4.20 (s, 3H), 2.00 (dd, J = 7.56, 15.22 Hz, 1H), 1.21 (d, J = 14.05 Hz, 4H). 436  98% 5-24

OMe Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 8.77 (s, 1H), 7.87 (d, J = 9.25 Hz, 1H), 7.75 (s, 1H), 7.20 (s, 1H), 7.14 (s, 1H), 4.17 (s, 3H), 3.47 (s, 3H), 1.32-1.05 (m, 8H). 412  96% 5-25

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.82 (s, 1H), 10.92 (s, 1H), 10.86 (s, 1H), 8.96 (s, 1H), 7.98 (t, J = 12.31 Hz, 1H), 7.15 (d, J = 7.60 Hz, 1H), 7.00 (d, J = 8.89 Hz, 2H), 4.44 (s, 1H), 2.67 (s, 3H), 1.28 (s, 2H), 1.12 (s, 2H). 394  98% 5-26

OMe Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.63 (s, 1H), 10.94 (s, 1H), 10.87 (s, 1H), 8.86 (s, 1H), 7.97 (d, J = 8.82 Hz, 1H), 7.17 (d, J = 7.41 Hz, 3H), 4.29 (s, 1H), 1.23 (s, 4H). 410  98% 5-27

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 8.95 (s, 1H), 7.96 (d, J = 8.75 Hz, 1H), 6.96 (d, J = 10.17 Hz, 1H), 6.92 (d, J = 8.04 Hz, 1H), 6.72 (d, J = 7.83 Hz, 1H), 4.44 (s, 1H), 3.63 (s, 2H), 3.09 (s, 2H), 2.70 (s, 3H), 1.30 (d, J = 5.29 Hz, 2H), 1.10 (s, 2H). 411  98% 5-28

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.74 (s, 1H), 8.89 (s, 1H), 7.94 (d, J = 8.48 Hz, 1H), 7.53 (s, 1H), 7.44 (s, 1H), 7.33 (d, J = 8.67 Hz, 1H), 6.94 (d, J = 8.45 Hz, 1H), 4.39 (s, 1H), 3.80 (s, 2H), 3.48 (s, 2H), 2.64 (s, 3H), 1.23 (s, 2H), 1.06 (s, 2H). 443  98% 5-29

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.67 (s, 1H), 10.84 (s, 1H), 8.83 (s, 1H), 7.86 (d, J = 8.65 Hz, 1H), 6.52 (s, 2H), 4.38 (s, 2H), 4.31 (s, 1H), 3.89 (s, 2H), 2.54 (s, 3H), 1.16 (s, 2H), 1.00 (s, 2H). 436  98% 5-30

OMe Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.71 (s, 1H), 10.91 (s, 1H), 8.79 (s, 1H), 7.88 (d, J = 9.15 Hz, 1H), 6.75 (d, J = 14.51 Hz, 2H), 4.45 (t, J = 4.51 Hz, 2H), 4.27- 4.16 (m, 1H), 3.96 (t, J = 4.53 Hz, 2H), 1.17 (d, J = 7.20 Hz, 4H). 452  99% 5-31

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 8.94 (s, 1H), 7.95 (d, J = 8.62 Hz, 1H), 6.79 (dd, J = 7.23, 14.68 Hz, 3H), 4.43 (s, 1H), 4.23 (d, J = 10.57 Hz, 1H), 4.06 (d, J = 10.42 Hz, 1H), 3.60-3.41 (m, 3H), 2.70 (s, 3H), 1.30 (d, J = 5.98 Hz, 2H), 1.09 (s, 2H). 425  99% 5-32

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 8.95 (s, 1H), 7.98 (d, J = 8.04 Hz, 1H), 7.09 (s, 1H), 6.96 (s, 2H), 4.44 (s, 1H), 4.15 (s, 2H), 3.29 (s, 3H), 2.69 (s, 3H), 2.02 (s, 2H), 1.30 (s, 2H), 1.10 (s, 2H). 409  99% 5-33

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 8.76 (s, 1H), 7.77 (d, J = 8.81 Hz, 1H), 6.59 (s, 3H), 4.25 (s, 1H), 4.04 (s, 2H), 3.27 (d, J = 11.94 Hz, 1H), 2.96-2.79 (m, 1H), 2.52 (s, 3H), 1.18 (t, J = 8.54 Hz, 3H), 1.12 (d, J = 5.48 Hz, 2H), 0.91 (s, 2H). 409  98% 5-34

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 8.71 (s, 1H), 7.72 (d, J = 8.62 Hz, 1H), 6.54 (s, 3H), 4.20 (s, 2H), 4.03 (d, J = 10.38 Hz, 2H), 3.52 (t, J = 8.97 Hz, 1H), 3.31 (s, 1H), 2.46 (s, 3H), 1.07 (d, J = 5.70 Hz, 2H), 0.96 (d, J = 4.88 Hz, 3H), 0.86 (s, 2H). 409  98% 5-35

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 10.57 (s, 1H), 8.89 (s, 1H), 7.93 (d, J = 8.73 Hz, 1H), 7.48 (d, J = 52.24 Hz, 1H), 6.96 (d, J = 7.83 Hz, 1H), 6.80 (s, 1H), 6.74 (d, J = 7.83 Hz, 1H), 4.38 (s, 1H), 3.76 (d, J = 12.76 Hz, 1H), 2.63 (s, 3H), 2.07 (s, 1H), 1.85 (s, 1H), 1.66 (s, 1H), 1.58-1.37 (m, 3H), 1.23 (d, J = 6.52 Hz, 2H), 1.06 (s, 2H). 462  98% 5-36

Cl Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 10.92 (s, 1H), 10.70 (s, 1H), 8.92 (s, 1H), 8.09 (d, J = 8.43 Hz, 1H), 7.82 (s, 1H), 7.04 (d, J = 22.18 Hz, 1H), 6.64 (d, J = 10.90 Hz, 2H), 4.52-4.28 (m, 3H), 4.01-3.82 (m, 2H), 1.20 (t, J = 10.03 Hz, 2H), 1.12 (d, J = 3.28 Hz, 2H). 456  97% 5-37

8-Me

¹H NMR (400 MHz, DMSO) δ 8.85 (d, J = 3.12 Hz, 1H), 7.90 (d, J = 8.88 Hz, 1H), 6.71 (d, J = 5.48 Hz, 3H), 5.23 (d, J = 3.10 Hz, 1H), 5.07 (d, J = 2.78 Hz, 1H), 4.42-4.27 (m, 1H), 4.22-4.12 (m, 2H), 2.55 (s, 3H), 1.74 (ddd, J = 8.97, 14.93, 17.91 Hz, 1H), 1.62- 1.45 (m, 1H). 413  98% 5-38

8-Me

¹H NMR (400 MHz, DMSO) δ 14.44 (d, J = 137.56 Hz, 2H), 10.82 (d, J = 68.59 Hz, 1H), 8.85 (t, J = 9.38 Hz, 1H), 7.93 (t, J = 10.51 Hz, 1H), 6.56 (t, J = 40.40 Hz, 2H), 4.44 (d, J = 4.54 Hz, 3H), 4.39-4.29 (m, 1H), 4.04-3.90 (m, 3H), 2.54 (s, 3H), 1.64 (m, 2H). 454  98% 5-39

Cl Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 8.92 (s, 1H), 8.10 (d, J = 8.56 Hz, 1H), 7.69 (s, 1H), 7.18 (s, 1H), 4.41 (s, 2H), 4.23-4.19 (m, 3H), 3.51 (s, 2H), 1.22 (d, J = 6.34 Hz, 2H), 1.11 (s, 2H). 416  98% 5-40

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.67 (s, 1H), 8.91 (s, 1H), 7.97 (d, J = 8.68 Hz, 1H), 7.35 (s, 1H), 6.99 (s, 1H), 4.68 (d, J = 4.53 Hz, 2H), 4.58 (d, J = 4.64 Hz, 2H), 4.40 (dd, J = 3.32, 6.77 Hz, 1H), 2.61 (s, 3H), 1.24 (d, J = 6.14 Hz, 2H), 1.10 (s, 2H). 434  98% 5-41

8- OMe

¹H NMR (400 MHz, DMSO) δ 14.59 (s, 1H), 10.91 (s, 1H), 8.82 (s, 1H), 7.89 (d, J = 9.04 Hz, 1H), 6.74 (d, J = 14.28 Hz, 2H), 5.08 (d, J = 64.31 Hz, 1H). 4.45 (s, 2H), 4.19 (s, 1H), 3.96 (s, 2H), 1.80 (d, J = 26.47 Hz, 1H), 1.65 (dd, J = 7.14, 16.55 Hz, 1H). 470  98% 5-42

8- OMe

¹H NMR (400 MHz, DMSO) δ 8.80 (s, 1H), 7.86 (d, J = 9.34 Hz, 1H), 6.87 (d, J = 8.16 Hz, 1H), 6.84 (s, 1H), 6.70 (d, J = 8.14 Hz, 1H), 5.18-4.96 (m, 1H), 4.17 (s, 3H), 3.36 (s, 2H), 1.84-1.58 (m, 2H). 429  98% 5-43

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.75-14.70 (s, 1H), 8.80-8.76 (s, 1H), 7.89-7.83 (d, J = 9.4 Hz, 1H), 6.92- 6.86 (d, J = 11.4 Hz, 1H), 6.77-6.73 (s, 1H), 6.16-6.10 (s, 1H), 4.27-4.15 (s, 3H), 3.47-3.41 (s, 3H), 3.40-3.34 (q, J = 3.6 Hz, 2H), 1.20-1.09 (dd, J = 14.4, 5.5 Hz, 4H). 429  90% 5-44

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.77-14.85 (s, 1H), 8.80-8.76 (s, 1H), 7.89-7.83 (d, J = 9.3 Hz, 1H), 7.09- 7.03 (t, J = 1.6 Hz, 1H), 6.90-6.84 (t, J = 1.6 Hz, 1H), 6.19-6.10 (s, 1H), 4.26-4.15 (m, 3H), 3.48-3.39 (s, 5H), 1.20-1.09 (ddd, J = 10.6, 5.5, 3.0 Hz, 4H). 445 100% 5-45

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 8.80-8.74 (s, 1H), 7.88-7.80 (d, J = 9.3 Hz, 1H), 6.81-6.71 (dd, J = 17.1, 2.1 Hz, 2H), 4.28-4.18 (tt, J = 7.2, 4.3 Hz, 1H), 4.18- 4.12 (t, J = 4.2 Hz, 2H), 3.44-3.35 (m, 5H), 2.16- 2.10 (s, 3H), 1.20-1.08 (m, 4H). 425 100% 5-46

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 8.79-8.75 (s, 1H), 7.87-7.81 (d, J = 9.3 Hz, 1H), 6.55-6.49 (s, 1H), 6.43- 6.39 (s, 1H), 4.27-4.18 (s, 1H), 4.16-4.10 (t, J = 4.3 Hz, 2H), 3.33-3.5 (s, 2H), 2.57-2.52 (s, 3H), 1.20-1.09 (m, 4H). 426  96% 5-47

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.83-14.56 (s, 1H), 8.81-8.77 (s, 1H), 8.66-8.59 (m, 1H), 7.95-7.89 (d, J = 9.3 Hz, 1H), 7.89-7.84 (t, J = 1.7 Hz, 1H), 7.24- 7.19 (s, 1H), 4.30-4.18 (m, 3H), 3.67-3.60 (q, J = 3.8 Hz, 2H), 3.52-3.44 (s, 3H), 1.20-1.12 (td, J = 6.5, 5.8, 2.7 Hz, 4H). 456 100% 5-48

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 15.22-14.17 (m, 1H), 8.97-8.90 (s, 1H), 8.84-8.80 (s, 1H), 7.97-7.90 (d, J = 9.0 Hz, 1H), 7.51-7.47 (s, 1H), 7.07-7.02 (s, 1H), 4.69-4.57 (s, 4H), 4.28-4.18 (p, J = 5.7 Hz, 1H), 3.42- 3.35 (s, 3H), 1.21-1.12 (d, J = 5.6 Hz, 4H). 436 100% 5-49

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.70-14.66 (s, 1H), 8.84-8.80 (s, 1H), 7.97-7.92 (d, J = 9.0 Hz, 1H), 7.78- 7.74 (s, 1H), 7.08-7.04 (s, 1H), 5.00-4.94 (t, J = 4.9 Hz, 2H), 4.82-4.74 (t, J = 4.8 Hz, 2H), 4.27-4.18 (p, J = 5.7 Hz, 1H), 3.43-3.38 (s, 3H), 1.21-1.13 (d, J = 5.6 Hz, 4H). 437  85% 5-50

OMe Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.72 (s, 1H), 8.94 (s, 1H), 7.87 (d, J = 9.4 Hz, 1H), 6.89 (d, J = 11.4 Hz, 1H), 6.75 (s, 1H), 6.13 (s, 1H), 4.21 (m, 3H), 3.40 (s, 3H), 1.31-0.94 (m, 4H). 429  90% 5-51

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.72 (s, 1H), 8.88 (s, 1H), 7.91 (d, J = 8.8 Hz, 1H), 6.91 (s, 1H), 6.72 (s, 1H), 6.07 (s, 1H), 4.48-4.30 (m, 1H), 4.20 (m, 2H), 3.43 (m, 2H), 2.70-2.56 (m, 3H), 1.24 (d, J = 4.0 Hz, 2H), 1.04 (s, 2H). 429  98% 5-52

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.5 (b, 1H), 8.91 (s, 1H), 8.86 (s, 1H), 7.97 (d, J = 8.8 Hz, 1H), 7.34 (s, 1H), 6.90 (s, 1H), 4.63 (s, 4H), 4.39 (mz, 1H), 2.61 (s, 3H), 1.24 (d, J = 4.6 Hz, 2H), 1.09 (s, 2H). 420  98% 5-53

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.73 (s, 1H), 8.88 (s, 1H), 7.90 (d, J = 8.8 Hz, 1H), 7.22 (s, 1H), 6.76 (s, 1H), 4.44-4.28 (m, 1H), 4.15 (m, 2H), 3.43 (m, 2H), 2.65 (s, 3H), 1.24 (s, 2H), 1.04 (s, 2H). 521  97% 5-54

Me Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 14.73 (s, 1H), 8.89 (s, 1H), 7.91 (d, J = 7.8 Hz, 1H), 6.75 (d, J = 11.3 Hz, 1H), 6.59 (s, 1H), 4.37 (m, 1H), 4.22 (s, 2H), 3.39 (s, 2H), 2.65 (s, 3H), 1.22 (m, 2H), 1.00 (m, 2H). 413  97% 5-55

Cl Cyclopropyl ¹H NMR (400 MHz, DMSO) δ 8.90 (s, 1H), 8.05 (d, J = 8.6 Hz, 1H), 6.91-6.49 (m, 3H), 4.46-4.36 (m, 1H), 4.16 (m, 2H), 3.49 (m, 2H), 2.67 (s, 3H), 1.19 (t, J = 15.1 Hz, 2H), 1.09 (s, 2H). 415  98% 5-56

¹H NMR (400 MHz, DMSO) δ 8.77 (s, 1H), 8.15 (d, J = 7.00 Hz, 1H), 7.24-7.02 (m, 2H), 6.78 (d, J = 8.23 Hz, 1H), 4.28-4.13 (m, 2H), 4.05-3.86 (m, 1H), 3.49- 3.34 (m, 2H), 2.90 (d, J = 2.66 Hz, 3H), 1.44-1.32 (m, 2H), 1.28-1.17 (m, 2H). 395  98% 5-57

¹H NMR (400 MHz, DMSO) δ 15.13 (s, 1H), 8.84 (s, 1H), 8.16 (d, J = 8.2 Hz, 1H), 7.71 (s, 1H), 7.20-7.06 (m, 2H), 6.73 (t, J = 16.6 Hz, 1H), 4.30 (m, 1H), 4.22- 4.17 (m, 2H), 3.68 (s, 2H), 3.44 (s, 3H), 1.43-0.95 (m, 4H). 393  98%

TABLE 6

Com- pound MS No. R³ = R² = NMR (MH⁺) HPLC 6-1

Me ¹H NMR (400 MHz, MeOD) δ 7.92 (s, 1H), 7.35 (m. 2H), 6.96 (s, 1H), 6.80 (m. 2H), 4.30- 4.19 (m, 1H), 3.75 (s, 3H), 2.59 (s, 3H), 0.96 (m, 2H), 0.79 (m, 2H). 368 98% 6-2

Me ¹H NMR (400 MHz, DMSO) δ 14.75 (s, 1H), 8.89 (s, 1H), 7.92 (d, J = 8.8 Hz, 1H), 7.50 (t, J = 7.7 Hz, 1H), 7.24 (dd, J = 15.3, 7.9 Hz, 2H), 7.14 (d, J = 7.4 Hz, 1H), 4.38 (m, 1H), 3.76 (s, 3H), 2.55 (s, 3H), 1.41-1.15 (m, 2H), 1.12-0.96 (m, 2H). 482 90% 6-3

Me ¹H NMR (400 MHz, DMSO) δ 14.80 (s, 1H), 8.95 (s, 1H), 8.00 (d, J = 8.8 Hz. 1H), 7.57 (d, J = 7.2 Hz, 2H), 7.49 (t, J = 7.3 Hz, 2H), 7.45-7.36 (m, 3H), 7.26 (d, J = 8.6 Hz, 2H), 5.25 (s, 2H), 4.54-4.32 (m, 1H), 2.67 (s, 3H), 1.30 (d, J = 6.2 Hz, 2H), 1.11 (s, 2H). 444 99% 6-4

Me ¹H NMR (400 MHz, DMSO) δ 14.76 (s, 1H), 8.90 (s, 1H), 7.94 (d, J = 8.5 Hz, 1H), 7.35 (d, J = 8.0 Hz, 2H), 7.12 (d, J = 8.2 Hz, 2H), 4.38 (s, 1H), 3.84 (s, 3H), 2.61 (s, 3H), 1.23 (d, J = 6.2 Hz, 2H), 1.05 (s, 2H). 368 96% 6-5

Me ¹H NMR (400 MHz, DMSO) δ 14.63 (s, 1H), 8.88 (s, 1H), 7.92 (d, J = 8.9 Hz, 1H), 7.31 (d, J = 8.4 Hz, 2H), 7.08 (d, J = 8.7 Hz, 2H), 4.71 (dt, J = 12.0, 6.0 Hz, 1H), 4.38 (m, 1H), 2.58 (d, J = 26.0 Hz, 3H), 1.32 (d, J = 6.0 Hz, 6H), 1.23 (q, J = 6.9 Hz, 2H), 1.02 (s, 2H). 396 99% 6-6

Me ¹H NMR (400 MHz, DMSO) δ 14.68 (s, 1H), 8.91 (s, 1H), 7.98 (d, J = 8.8 Hz, 1H), 7.58 (s, 4H), 4.52-4.24 (m, 1H), 2.60 (s, 3H), 1.23 (q, J = 7.0 Hz, 2H), 1.15-1.01 (m, 2H). 422 99% 6-7

Me ¹H NMR (400 MHz, DMSO) δ 14.66 (s, 1H), 8.91 (s, 1H), 7.99 (d, J = 8.8 Hz, 1H), 7.72 (t, J = 7.9 Hz, 1H), 7.54 (d, J = 8.3 Hz, 1H), 7.52-7.44 (m, 2H), 4.52-4.20 (m, 1H), 2.60 (s, 3H), 1.23 (d, J = 6.8 Hz, 2H), 1.08 (s, 2H). 422 99% 6-8

Me ¹H NMR (400 MHz, DMSO) δ 14.48 (s, 1H), 8.76 (s, 1H), 7.86 (d, J = 8.7 Hz, 1H), 7.60- 7.52 (m, 1H), 7.45 (ddd, J = 10.9, 9.8, 4.6 Hz, 3H), 4.25 (dt, J = 10.7, 3.6 Hz, 1H), 2.43 (s, 3H), 1.06 (dq, J = 9.4, 7.1 Hz, 2H), 0.99-0.71 (m, 3H). 422 99% 6-9

Me ¹H NMR (400 MHz, DMSO) δ 14.64 (s, 1H), 8.83 (s, 1H), 7.87 (d, J = 8.7 Hz, 1H), 6.61 (s, 2H), 4.33 (m, 1H), 3.74 (s, 6H), 3.68 (s, 3H), 2.57 (s, 3H), 1.18 (d, J = 6.4 Hz, 2H), 1.01 (s, 2H). 428 95% 6-10

Me ¹H NMR (400 MHz, DMSO) δ 14.80 (s, 1H), 8.88 (s, 1H), 7.90 (d, J = 8.6 Hz, 1H), 7.17 (d, J = 8.3 Hz, 1H), 6.76 (d, J = 2.2 Hz, 1H), 6.70 (dd, J = 8.4, 2.3 Hz, 1H), 4.47-4.28 (m, 1H), 3.85 (s, 3H), 3.75 (s, 3H), 2.55 (s, 3H), 1.21 (dd, J = 6.7, 4.5 Hz, 2H), 1.02 (dd, J = 10.3, 4.5 Hz, 2H). 398 96% 6-11

Me ¹H NMR (400 MHz, DMSO) δ 14.70 (s, 1H), 8.80 (s, 1H), 7.86 (d, J = 8.1 Hz, 1H), 7.32 (m, 2H), 7.16 (d, J = 7.2 Hz, 1H), 4.25 (s, 1H), 3.92 (s, 3H), 2.57 (s, 3H), 1.41-1.10 (m, 2H), 0.89 (m, 2H). 386 96% 6-12

Me ¹H NMR (400 MHz, DMSO) δ 14.74 (s, 1H), 8.90 (s, 1H), 7.93 (d, J = 8.8 Hz, 1H), 7.13 (d, J = 8.3 Hz, 1H), 6.97 (s, 1H), 6.93 (dd, J = 8.2, 1.7 Hz, 1H), 4.39 (tt, J = 7.1, 3.8 Hz, 1H), 3.84 (s, 3H), 3.79 (s, 3H), 2.63 (s, 3H), 1.24 (d, J = 6.8 Hz, 2H), 1.07 (s, 2H). 398 99% 6-13

Me ¹H NMR (400 MHz, DMSO) δ 14.70 (s, 1H), 8.90 (s, 1H), 7.94 (d, J = 8.7 Hz, 1H), 7.54 (s, 1H), 7.35 (dd, J = 18.3, 8.3 Hz, 2H), 4.39 (m, 1H), 3.95 (s, 3H), 2.62 (s, 3H), 1.23 (d, J = 5.8 Hz, 2H), 1.06 (s, 2H). 402 99% 6-14

Me ¹H NMR (400 MHz, DMSO) δ 14.69 (s, 1H), 8.91 (s, 1H), 7.97 (d, J = 8.6 Hz, 1H), 7.72 (d, J = 8.6 Hz, 1H), 7.67 (s, 1H), 7.47 (d, J = 8.6 Hz, 1H), 4.40 (m, 1H), 3.99 (s, 3H), 2.61 (s, 3H), 1.24 (d, J = 5.6 Hz, 2H), 1.08 (s, 2H). 436 99% 6-15

Me ¹H NMR (400 MHz, DMSO) δ 14.76 (s, 1H), 8.89 (s, 1H), 7.93 (d, J = 8.5 Hz, 1H), 7.20 (d, J = 12.7 Hz, 2H), 7.11 (d, J = 8.0 Hz, 1H), 4.38 (m, 1H), 3.87 (s, 3H), 2.64 (s, 3H), 2.23 (s, 3H), 1.23 (m, 2H), 1.07 (m, 2H). 382 99% 6-16

Me ¹H NMR (400 MHz, DMSO) δ 14.78 (s, 1H), 8.88 (s, 1H), 7.91 (d, J = 8.6 Hz, 1H), 6.95 (d, J = 7.4 Hz, 1H), 6.62 (s, 1H), 6.52 (d, J = 6.8 Hz, 1H), 4.94 (s, 2H), 4.39 (s, 1H), 3.84 (s, 3H), 2.63 (s, 3H), 1.23 (s, 2H), 1.03 (s, 2H). 383 95% 6-17

Me ¹H NMR (400 MHz, DMSO) δ 14.66 (s, 1H), 10.16 (s, 1H), 8.91 (s, 1H), 7.96 (d, J = 8.9 Hz, 2H), 7.26 (dd, J = 28.6, 8.1 Hz, 2H), 4.39 (m, 1H), 4.24 (m, 2H), 3.86 (m, 4H), 3.33 (m, 4H), 2.63 (s, 3H), 1.22 (d, J = 6.1 Hz, 2H), 1.05 (s, 2H). 510 90% 6-18

Me ¹H NMR (400 MHz, DMSO) δ 14.73 (s, 1H), 9.12 (s, 1H), 8.90 (s, 1H), 7.95 (d, J = 9.0 Hz, 1H), 7.29 (s, 1H), 7.26 (s, 2H), 4.39 (m, 1H), 3.92 (s, 3H), 3.01 (s, 3H), 2.62 (s, 3H), 1.35- 1.15 (m, 2H), 1.06 (m, 2H). 461 98% 6-19

Me ¹H NMR (400 MHz, DMSO) δ 14.76 (s, 1H), 8.89 (s, 1H), 8.14 (d, J = 14.8 Hz, 2H), 7.94 (d, J = 8.9 Hz, 1H), 7.14 (d, J = 8.3 Hz, 1H), 6.90 (d, J = 7.9 Hz, 1H), 6.28 (s, 2H), 4.39 (s, 1H), 3.93 (s, 3H), 2.65 (s, 3H), 1.19 (m, 2H), 1.04 (m, 2H). 426 98% 6-20

Me ¹H NMR (400 MHz, DMSO) δ 14.73 (s, 1H), 8.91 (s, 1H), 7.97 (d, J = 8.7 Hz, 1H), 7.56 (d, J = 6.9 Hz, 2H), 7.31 (d, J = 8.5 Hz, 1H), 4.39 (m, 1H), 3.91 (s, 3H), 2.62 (s, 3H), 1.52 (s, 9H), 1.24 (m, 2H), 1.07 (m, 2H). 468 98% 6-21

Me ¹H NMR (400 MHz, DMSO) δ 14.80 (s, 1H), 12.93 (s, 1H), 8.97 (s, 1H), 8.02 (d, J = 8.8 Hz, 1H), 7.70 (s, 1H), 7.82 (d, J = 8.3 Hz, 1H), 7.38 (d, J = 0.8 Hz, 1H), 4.39 (m, 1H), 3.67 (s, 3H), 2.62 (s, 3H), 1.52 (s, 9H), 1.30 (m, 2H), 1.13 (m, 2H). 412 98% 6-22

Me ¹H NMR (400 MHz, DMSO) δ 14.72 (s, 1H), 8.92 (s, 1H), 8.52 (s, 1H), 7.97 (d, 8.3 Hz, 1H), 7.81 (s, 3H), 7.57 (d, J = 7.9 Hz, 1H), 7.36 (d, J = 8.4 Hz, 1H), 4.39 (s, 1H), 3.96 (d, J = 24.7 Hz, 3H), 3.84 (s, 2H), 2.99 (s, 2H), 2.69-2.54 (m, 3H), 1.23 (d, J = 5.3 Hz, 2H), 1.07 (s, 2H). 454 95% 6-24

Me ¹H NMR (400 MHz, DMSO) δ 14.72 (s, 1H), 9.40 (s, 1H), 8.92 (s, 1H), 8.80 (s, 1H), 7.99 (s, 1H), 7.81 (s, 1H), 7.57 (s, 1H), 7.38 (s, 1H), 4.40 (s, 1H), 4.00 (s, 3H), 3.66 (s, 2H), 3.28 (s, 2H), 2.85 (s, 6H), 2.61 (s, 3H), 1.24 (s, 2H), 1.07 (s, 2H). 482 99% 6-25

Me ¹H NMR (400 MHz, DMSO) δ 14.73 (s, 1H), 8.91 (s, 1H), 8.37 (s, 1H), 7.96 (d, J = 8.3 Hz, 1H), 7.75 (s, 1H), 7.53 (d, J = 8.2 Hz, 1H), 7.33 (d, J = 8.4 Hz, 1H), 6.95 (s, 1H), 4.40 (s, 1H), 3.98 (s, 3H), 3.33 (d, J = 5.1 Hz, 2H), 3.13 (d, J = 5.4 Hz, 2H), 2.61 (s, 3H), 1.36 (s, 9H), 1.24 (d, J = 4.4 Hz, 2H), 1.07 (s, 2H). 554 95% 6-26

Me ¹H NMR (400 MHz, DMSO) δ 14.72 (s, 1H), 10.43 (s, 1H), 8.91 (s, 1H), 7.97 (d, J = 8.7 Hz, 1H), 7.74 (d, J = 8.8 Hz, 1H), 7.70 (s, 1H), 7.45 (d, J = 8.6 Hz, 1H), 4.39 (m, 1H), 4.02 (s, 3H), 2.61 (s, 3H), 1.23 (m, 2H), 1.07 (m, 2H). 396 98% 6-27

Me ¹H NMR (400 MHz, DMSO) δ 14.65 (s, 1H), 8.91 (s, 1H), 8 47 (s, 1H), 7.97 (d, J = 8.7 Hz, 1H), 7.71 (s, 1H), 7.66 (s, 1H), 7.44 (d, J = 8.7 Hz, 1H), 7.38 (d, J = 8.6 Hz, 1H), 4.40 (m, 1H), 4.05 (s, 3H), 2.65 (s, 3H), 1.25 (d, J = 6.7 Hz, 2H), 1.08 (s, 2H). 435 90% 6-28

Me ¹H NMR (400 MHz, DMSO) 14.71 (s, 1H), 8.90 (s, 1H), 7.96 (d, J = 8.4 Hz, 1H), 7.40 (d, J = 11.8 Hz, 2H), 7.26 (d, J = 8.0 Hz, 1H), 4.39 (s, 1H), 3.94 (s, 5H), 2.62 (s, 3H), 1.23 (s, 2H), 1.06 (s, 2H). 407 95% 6-29

Me ¹H NMR (400 MHz, DMSO) δ 14.68 (s, 1H), 10.43 (s, 1H), 8.91 (s, 1H), 7.97 (d, J = 8.8 Hz, 1H), 7.86-7.62 (m, 2H), 7.44 (d, J = 8.5 Hz, 1H), 4.39 (s, 1H), 4.02 (s, 2H), 2.64 (s, 3H), 1.23 (s, 2H), 1.07 (s, 2H). 396 95% 6-30

Me ¹H NMR (400 MHz, DMSO) δ 14.66 (s, 2H), 8.93 (s, 1H), 8.33 (s, 1H), 8.02 (d, J = 8.6 Hz, 1H), 7.80 (s, 2H), 7.71 (d, J = 8.5 Hz, 1H), 7.56 (d, J = 8.4 Hz, 1H), 7.46 (s, 2H), 4.42 (s, 1H), 4.17 (s, 3H), 2.66 (s, 3H), 1.35-1.15 (m, 2H), 1.09 (s, 2H). 484 85% 6-31

Me ¹H NMR (400 MHz, DMSO) δ 14.74 (s, 1H), 11.37 (s, 1H), 8.90 (s, 1H), 8.35 (s, 1H), 7.96 (d, J = 8.1 Hz, 1H), 7.64 (s, 1H), 7.43 (d, J = 8.1 Hz, 1H), 7.27 (d, J = 8.5 Hz, 1H), 4.39 (s, 1H), 3.92 (s, 3H), 2.63 (s, 3H), 1.23 (d, J = 5.2 Hz, 2H), 1.06 (s, 2H). 411 95% 6-32

Me ¹H NMR (400 MHz, DMSO) δ 14.75 (s, 1H), 8.91 (s, 1H), 7.97 (d, J = 3.7 Hz, 1H), 7.78 (s, 2H), 7.70 (s, 1H), 7.54 (d, J = 8.2 Hz, 1H), 7.33 (d, J = 8.4 Hz, 1H), 4.40 (s, 1H), 3.98 (s, 3H), 2.61 (s, 3H), 1.23 (s, 2H), 1.07 (s, 2H). 411 94% 6-33

Me ¹H NMR (400 MHz, DMSO) δ 14.73 (s, 1H), 8.92 (s, 1H), 7.96 (d, J = 8.6 Hz, 1H), 7.37 (s, 2H), 7.23 (d, J = 7.3 Hz, 1H), 4.39 (m, 1H), 3.89 (s, 3H), 3.74 (m, 4H), 3.07 (s, 4H), 2.76 (s, 3H), 2.62 (s, 3H), 1.24 (s, 2H), 1.06 (s, 2H). 480 96% 6-34

Me ¹H NMR (400 MHz, DMSO) δ 14.73 (s, 1H), 8.92 (s, 1H), 8.87 (s, 1H), 7.97 (d, J = 8.1 Hz, 1H), 7.48 (s, 2H), 7.29 (d, J = 8.7 Hz, 1H), 4.40 (m, 1H), 4.18 (s, 2H), 3.94 (s, 3H), 2.63 (s, 3H), 2.55 (s, 3H), 1.24 (s, 2H), 1.05 (s, 2H). 411 86% 6-35

Me ¹H NMR (400 MHz, DMSO) δ 14.69 (s, 1H), 8.91 (s, 1H), 7.97 (d, J = 8.6 Hz, 1H), 7.91 (s, 1H), 7.75 (d, J = 8.1 Hz, 1H), 7.44 (d, J = 8.1 Hz, 1H), 4.39 (s, 1H), 4.02 (s, 3H), 2.61 (s, 3H), 1.23 (s, 2H), 1.07 (s, 2H). 393 95% 6-36

Me ¹H NMR (400 MHz, DMSO) δ 14.78 (s, 1H), 8.90 (s, 1H), 7.95 (d, J = 8.7 Hz, 1H), 7.37 (s, 1H), 7.26 (d, J = 8.0 Hz, 1H), 7.13 (d, J = 8.3 Hz, 1H), 5.18 (s, 1H), 4.57 (s, 2H), 4.39 (s, 1H), 3.87 (s, 3H), 2.62 (s, 3H), 1.23 (s, 2H), 1.05 (s, 2H). 398 95% 6-37

Me ¹H NMR (400 MHz, DMSO) δ 14.71 (s, 1H), 9.63 (s, 1H), 8.92 (s, 1H), 8.51 (s, 1H), 7.98 (d, J = 8.5 Hz, 1H), 7.67 (s, 1H), 7.52 (d, J = 8.3 Hz, 1H), 7.32 (d, J = 8.5 Hz, 1H), 4.43 (m, 3H), 3.94 (s, 3H), 3.43 (s, 2H), 2.80 (d, J = 24.7 Hz, 6H), 2.62 (s, 3H), 1.23 (s, 2H), 1.07 (s, 2H). 482 95% 6-38

Me ¹H NMR (400 MHz, DMSO) δ 14.74 (s, 1H), 8.90 (s, 1H), 7.93 (d, J = 9.2 Hz, 1H), 7.10 (d, J = 8.0 Hz, 1H), 7.02 (s, 1H), 6.86 (d, J = 8.0 Hz, 1H), 6.13 (s, 2H), 4.38 (m, 1H), 2.62 (s, 3H), 1.23 (m, 2H), 1.05 (m, 2H). 382 98% 6-39

Me ¹H NMR (400 MHz, DMSO) δ 14.67 (s, 1H), 10.11 (s, 1H), 8.91 (s, 1H), 7.97 (d, J = 8.7 Hz, 1H), 7.33 (d, J = 1.6 Hz, 1H), 7.29 (d, J = 1.6 Hz, 1H), 6.45-6.21 (s, 2H), 4.41-4.30 (m, 1H), 2.74-2.56 (s, 3H), 1.33-1.17 (d, J = 6.6 Hz, 2H), 1.12-0.96 (t, J = 3.1 Hz, 2H). 410 98% 6-40

Me ¹H NMR (400 MHz, DMSO) δ 14.69 (s, 1H), 11.53 (s, 1H), 8.90 (s, 1H), 8.16 (s, 1H), 7.95 (d, J = 8.7 Hz, 1H), 7.08 (d, J = 1.7 Hz, 1H), 7.02 (d, J = 1.7 Hz, 1H), 6.21 (s, 2H), 4.48- 4.16 (m, 1H), 2.64 (s, 3H), 1.35-1.21 (d, J = 6.8 Hz, 2H), 1.12-1.01 (m, 2H). 425 98% 6-41

Me ¹H NMR (400 MHz. DMSO) δ 14.64 (s, 1H), 8.90 (s, 1H), 7.96 (d, J = 8.8 Hz. 1H), 7.36 (d, J = 1.6 Hz, 1H), 7.4 (d, J = 1.6 Hz, 1H), 6.36 (s, 2H), 4.52-4.26 (m, 1H), 2.63 (s, 3H), 1.35- 1.15 (d, J = 6.6 Hz, 2H), 1.10-0.99 (m, 2H). 407 98% 6-42

Me ¹H NMR (400 MHz, DMSO) δ 14.68 (s, 1H), 8.89 (s, 1H), 794 (d, J = 8.7 Hz. 1H), 7.06 (d, J = 1.5 Hz, 1H), 6.95 (d, J = 1.5 Hz, 1H), 6.22 (s, 2H), 4.57-4.46 (s, 1H), 4.42-4.30 (m, 1H), 2.63 (s, 3H), 1.33-1.15 (d, J = 6.2 Hz, 2H), 1.12-0.90 (m, 1H). 406 95% 6-43

OMe ¹H NMR (400 MHz, DMSQ) δ 14.70 (s, 1H), 8.80 (s, 1H), 7.90 (d, J = 9.1 Hz, 1H), 7.06 (s, 1H), 7.01 (s, 1H), 8.13 (s, 2H), 5.31 (t, J = 5.6 Hz, 1H), 4.54 (d, J = 5.6 Hz, 2H), 4.34-4.12 (mz, 1H), 3.44 (s, 3H), 1.33-0.99 (m, 4H). 428 97% 6-44

Me ¹H NMR (400 MHz, DMSO) δ 14.69 (s, 1H), 8.89 (s, 1H), 7.93 (d, J = 8.7 Hz, 1H), 6.97 (s, 1H), 6.93 (s, 1H), 6.73 (dd, J = 17.7, 11.3 Hz, 1H), 6.20 (s, 2H), 6.00 (d, J = 17.6 Hz, 1H), 5.49 (d, J = 11.5 Hz, 1H), 4.53-4.25 (m, 1H), 2.75-2.57 (s, 3H), 1.32-1.17 (d, J = 6.7 Hz, 2H), 1.11-0.89 (s, 2H). 408 95% 6-45

OMe ¹H NMR (400 MHz, DMSO) δ 14.66 (s, 1H), 8.80 (s, 1H), 7.90 (d, J = 9.1 Hz, 1H), 7.17 (s, 1H), 7.09 (s, 1H), 6.23 (s, 2H), 4.49 (s, 1H), 4.34-4.14 (m, 1H), 3.47-3.42 (s, 3H), 1.31- 0.96 (m, 4H). 422 98% 6-46

OMe ¹H NMR (400 MHz, DMSO) δ 14.62 (s, 1H), 8.81 (s, 1H), 7.93 (d, J = 9.1 Hz, 1H), 7.45 (s, 1H), 7.44 (s, 1H), 6.36 (s, 2H), 4.39-4.04 (m, 1H), 3.46 (s, 3H), 1.26-1.06 (m, 4H). 423 98% 6-47

OMe ¹H NMR (400 MHz, DMSO) δ 14.65 (s, 1H), 8.80 (s, 1H), 7.92 (d, J = 9.1 Hz, 1H), 7.30 (s, 1H), 7.19 (s, 11H), 7.17 (t, J = 56 Hz, 1H), 6.27 (s, 2H), 4.33-4.17 (m, 1H), 3.45 (s, 3H), 1.29-0.97 (m, 4H). 448 92% 6-48

OMe ¹H NMR (400 MHz, DMSO) δ 14.67 (s, 1H), 8.80 (s, 1H), 7.93 (d, J = 9.1 Hz, 1H), 7.77 (s, 1H), 7.42 (t, J = 1.4 Hz, 1H), 7.28 (t, J = 1.3 Hz, 1H), 7.25 (s, 1H), 6.27 (s, 2H), 4.33-4.13 (m, 1H), 3.449 (s, 3H), 1.37-0.87 (m, 4H). 441 98% 6-49

OMe ¹H NMR (400 MHz, DMSO) δ 14.66 (s, 1H), 10.12 (d, J = 1.2 Hz, 1H), 8.81 (s, 1H), 7.93 (d, J = 9.5 Hz, 1H), 7.44 (s, 1H), 7.42 (s, 1H), 6.35 (s, 2H), 4.33-4.17 (m, 1H), 3.46 (s, 3H), 1.32-0.97 (m, 4H). 426 98% 6-50

OMe ¹H NMR (400 MHz, DMSO) δ 14.68 (s, 1H), 8.80 (s, 1H), 7.89 (d, J = 9.1 Hz, 1H), 6.83- 6.80 (t, J = 1.3 Hz, 1H), 6.80-6.76 (t, J = 1.2 Hz, 1H), 6.11 (s, 2H), 4.34-4.12 (m, 1H), 3.86 (s, 3H), 3.31 (s, 3H), 1.26-1.02 (m, 4H). 428 98% 6-51

OMe ¹H NMR (400 MHz, DMSO) δ 14.70-14.61 (s, 1H), 8.84-8.78 (s, 1H), 7.96-7.88 (d, J = 9.0 Hz, 1H), 7.14 (s, 1H), 7.13 (s, 1H), 6.33-6.22 (s, 2H), 4.26-4.18 (m, 1H), 3.47 (s, 3H), 1.20-1.11 (m. 4H). 432 95% 6-52

OMe ¹H NMR (400 MHz, DMSO) δ 14.67 (s, 1H), 8.80 (s, 1H), 7.92 (d, J = 9.1 Hz, 1H), 7.77 (s, 1H), 7.42 (s, 1H), 7.28 (s, 1H), 7.25 (s, 1H), 6.27 (s, 2H), 4.22 (m, 1H), 3.44 (s, 3H), 1.17 (m, 4H). 441 85% 6-53

¹H NMR (400 MHz, DMSO) δ 14.49 (s, 1H), 8.83 (s, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.42 (s, 1H), 6.36 (s, 2H), 5.10 (m, 1H), 4.18 (m, 1H), 3.47 (s, 3H), 1.82-1.63 (m, 4H). 441 98% 6-54

¹H NMR (400 MHz, DMSO) δ 14.50 (s, 1H), 11.55 (s, 1H), 8.83 (s, 1H), 8.16 (s, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.27 (s, 1H), 7.10 (s, 1H), 6.22 (s, 1H), 5.10 (m, 1H), 4.18 (m, 1H), 3.47 (s, 3H), 1.82-1.63 (m, 4H). 459 95% 6-55

¹H NMR (400 MHz, DMSO) δ 14.47 (s, 1H), 8.82 (s, 1H), 8.10 (d, J = 8.7 Hz, 1H), 8.00- 7.87 (m, 1H), 7.65 (t, J = 9.4 Hz, 1H), 7.37 (t, J = 8.3 Hz, 1H), 7.21 (d, J = 8.0 Hz, 2H), 7.06 (d, J = 8.1 Hz, 2H), 3.81 (s, 3H). 440 99% 6-56

¹H NMR (400 MHz, DMSO) δ 15.44-15.10 (s, 1H), 9.12-8.99 (t, J = 1.7 Hz, 1H), 8.03- 7.92 (dt, J = 8.4, 1.8 Hz, 1H), 7.67-7.56 (dd, J = 8.6, 2.5 Hz, 3H), 7.16-6.98 (m, 2H), 5.03-4.89 (d, J = 7.3 Hz, 1H), 4.60-4.47 (d, J = 11.4 Hz, 1H), 4.44-4.33 (d, J = 11.5 Hz, 1H), 3.86-3.75 (t, J = 1.7 Hz, 3H), 1.53- 1.42 (d, J = 6.3 Hz, 3H). 352 99%

TABLE 7

Com- pound MS No. R¹⁶ = R² = NMR (MH⁺) HPLC 7-1 H Me ¹H NMR (400 MHz, DMSO) δ 14.74 (s, 1H), 8.90 (s, 344 100% 1H), 7.95 (d, J = 9.3 Hz, 1H), 7.80 (s, 2H), 7.27 (s, 1H), 4.39 (s, 1H), 2.68 (s, 3H), 1.23 (S, 3H), 1.03 (s, 2H). 7-2

Me ¹H NMR (400 MHz, DMSO) δ 14.69 (s, 1H), 9.37 (s, 2H), 8.91 (s, 1H), 7.96 (d, J = 8.9 Hz, 1H), 7.87 (s, 1H), 7.51 (s, 1H), 4.43 (s, 3H), 3.00 (d, J = 6.2 Hz, 2H), 2.71 (s, 3H), 1.24 (d, J = 6.4 Hz, 5H), 1.03 (s, 2H). 401  95% 7-3

Me ¹H NMR (400 MHz, DMSO) δ 14.70 (s, 1H), 13.87 (s, 1H), 8.91 (s, 1H), 7.98 (d, J = 8.1 Hz, 2H), 7.60 (s, 1H), 4.41 (s, 1H), 2.70 (s, 3H), 1.23 (s, 2H), 1.06 (s, 2H). 412 100% 7-4 CH₂CN Me ¹H NMR (400 MHz, DMSO) δ 14.75 (s, 1H), 8.90 (s, 383  97% 1H), 7.95 (d, J = 8.8 Hz, 1H), 7.76 (s, 1H), 7.22 (s, 1H), 5.76 (s, 2H), 4.40 (m, 1H), 2.69 (s, 3H), 1.23 (m, 2H), 1.04 (s, 2H). 7-5 CHO Me ¹H NMR (400 MHz, DMSO) δ 14.67 (s, 1H), 10.03 (s, 372  98% 1H), 8.92 (s, 1H), 8.39 (s, 1H), 8.23 (s, 1H), 7.99 (d, J = 9.1 Hz, 1H), 4.42 (s, 1H), 2.71 (s, 3H), 1.24 (d, J = 6.4 Hz, 2H), 1.05 (s, 2H). 7-6

Me ¹H NMR (400 MHz, DMSO) δ 14.70 (s, 1H), 11.34 (d, J = 16.3 Hz, 1H), 8.90 (s, 1H), 8.40 (s, 1H), 7.96 (d, 8.6 Hz, 1H), 7.78 (s, 1H), 7.42 (d, J = 14.9 Hz, 1H), 4.40 (s, 1H), 2.71 (s, 3H), 1.24 (d, J = 5.8 Hz. 2H), 1.04 (s, 2H). 387  96% 7-7

Me ¹H NMR (400 MHz, DMSO) δ 13.57-13.17 (m, 1H), 11.49 (s, 1H), 9.30 (s, 1H), 8.77 (s, 1H), 8.09 (s, 1H), 7.90 (d, J = 9.3 Hz, 1H), 7.83 (s, 1H), 4.33 (s, 1H), 2.66 (s, 3H), 1.22 (d, J = 7.5 Hz, 2H), 0.97 (s. 2H). 403 100% 7-8 CONH₂ Me ¹H NMR (400 MHz, DMSO) δ 14.70 (s, 1H), 8.91 (s, 387 100% 1H), 8.12 (s, 1H), 7.98 (m, 2H), 7.89 (s, 1H), 7.57 (s, 1H), 4.41 (s, 1H), 2.71 (s, 3H), 1.25 (d, J = 5.7 Hz, 2H), 1.03 (s, 2H). 7-9 CO₂H Me ¹H NMR (400 MHz, DMSO) δ 14.69 (s, 1H), 13.34 (s, 388 100% 1H), 8.91 (s, 1H), 8.12 (s, 1H), 7.96 (d, J = 8.7 Hz, 1H), 7.86 (s, 1H), 4.40 (s, 1H), 2.69 (s, 3H), 1.24 (d, J = 6.2 Hz, 2H), 1.05 (s, 2H). 7-10

Me ¹H NMR (400 MHz, DMSO) δ 14.68 (s, 1H), 12.49 (s, 1H), 8.87 (s, 1H), 7.96 (d, J = 11.9 Hz, 2H), 7.81 (d, J = 15.8 Hz, 1H), 7.69 (s, 1H), 6.30 (d, J = 15.7 Hz, 1H), 4.40 (s, 1H), 2.71 (s, 3H), 1.24 (d, J = 6.4 Hz, 2H), 1.04 (s, 2H). 414  95% 7-11

Me ¹H NMR (400 MHz, DMSO) δ 14.69 (s, 1H), 8.92 (s, 1H), 8 13 (s, 1H), 8.00 (d, J = 8.7 Hz, 1H), 7.91 (s, 1H), 4.42 (s, 1H), 2.74 (s, 3H), 1.24 (s, 2H), 1.06 (s, 2H). 412 100% 7-12

Me ¹H NMR (400 MHz, DMSO) δ 14.75 (s, 1H), 11.75 (s, 1H), 8.90 (s, 1H), 7.97 (s, 1H), 7.58 (s, 1H), 7.46 (s, 1H), 7.26 (s, 1H), 7.13 (s, 1H), 7.00 (s, 2H), 4.41 (s, 1H), 4.17 (d, J = 6.9 Hz, 2H), 2.75 (s, 3H), 1.99 (s, 2H), 1.23 (s, 3H), 1.04 (s, 2H), 0.85 (s, 2H). 481 100% 7-13

Me ¹H NMR (400 MHz, DMSO) δ 14.70 (s, 1H), 8.91 (s, 1H), 8.49 (s, 1H), 7.97 (d, J = 8.7 Hz, 1H), 7.91 (s, 1H), 7.64 (s, 2H), 4.41 (s, 1H), 2.73 (s, 3H), 1.25 (d, J = 8.5 Hz, 2H), 1.05 (s, 2H). 411  95% 7-14

Me ¹H NMR (400 MHz, DMSO) δ 14.90-14.40 (m, 1H), 8.83 (s, 1H), 8.05 (s, 1H), 8.02 (d, J = 8.4 Hz, 2H), 7.63 (s, 2H), 7.28 (s, 2H), 4.44 (s, 1H), 2.78 (s, 3H), 1.27 (d, J = 6.4 Hz, 2H), 1.07 (s, 2H). 460 100% 7-15

Me ¹H NMR (400 MHz, DMSO) δ 8.92 (s, 1H), 8.07 (d, J = 8.7 Hz, 2H), 7.99 (d, J = 8.8 Hz, 1H), 7.91 (s, 1H), 7.79 (s, 1H), 7.54 (s, 3H), 4.42 (s, 1H), 2.73 (s, 3H), 1.26 (d, J = 6.0 Hz, 3H), 1.07 (m, 2H). 487  95% 7-16

Me ¹H NMR (400 MHz, DMSO) δ 14.68 (b, 1H), 13.75 (s, 1H), 8.90 (s, 1H), 7.96 (d, 8.9 Hz, 1H), 7.77 (s, 1H), 7.61 (s, 1H), 4.47-4.32 (m, 1H), 2.73 (s, 3H), 2.41 (s, 3H), 1.25 (t, J = 6.3 Hz, 2H), 1.07 (s, 2H). 425  98% 7-17 CN OMe ¹H NMR (400 MHz, DMSO) δ 14.63 (s, 1H), 8.80 (s, 385  98% 1H), 8.42 (s, 1H), 7.28 (s, 1H), 7.96 (d, 9.2 Hz, 1H), 4.47-4.32 (m, 1H), 3.47 (s, 3H), 1.23-1.15 (m, 4H). 7-18

OMe ¹H NMR (400 MHz, DMSO) δ 8.57 (s, 1H), 7.72 (s, 2H), 7.58 (s, 1H), 7.43 (d, J = 9.7 Hz, 1H), 4.13 (m, 1H), 3.27 (s, 3H), 2.20 (s, 3H), 1.05-0.81 (m, 4H). 441  98% 7-19

Cl ¹H NMR (400 MHz, DMSO) δ 8.93 (s, 1H), 8.13 (d, J = 8.0 Hz, 1H), 7.86 (s, 1H), 7.67 (s, 1H), 4.13 (m, 1H), 2.40 (s, 3H), 1.24-1.12 (m, 4H). 445  85%

TABLE 8-1

Compound No. R¹⁹= R²= MS(MH⁺) 8-1 H Me 352.36 8-2 3-NH2 Me 337.34 8-3 4-F Me 355.33 8-4 4-CO2H Me 381.35 8-5 2-NH2 Me 352.36 8-6 3-Me Me 351.37 8-7 4-Me Me 351.37 8-8 2,3-Dimethyl Me 365.4 8-9 2-Cl Me 371.79 8-10 4-Cl Me 371.79 8-11 3-CO2H Me 381.35 8-12 3-CF3 Me 405.34 8-13 3,4-Dichloro Me 406.23 8-14 3-F Me 355.33 8-15 4-tBu Me 393.45 8-16 4-MeO Cyclopropyl 393.41 8-17 4-Ph Me 413.44 8-18 4-NO2 Me 382.34 8-19 3,4-Dichloro MeO 404.24 8-20 4-MeO Me 365.38 8-21 3,4-Dimethyl Me 365.4 8-22 4-CF3 Me 405.34 8-24 3-CONH2 Me 380.37 8-25 4-NH2 Me 352.36 8-26 4-OH Me 353.34 8-27 4-OMe F 353.34 8-28 4-OMe NO2 398.34 8-29 4-OMe Cl 387.79 8-30 4-OMe NH2 368.36 8-31 4-OMe Br 432.24 8-32 4-OMe H 353.34 8-33 4-OMe CN 378.35 8-34 4-OMe CH2F 385.36 8-35 4-OMe MeO 383 37 8-36 4-OMe CH2Br 446.27 8-37 4-OMe CH2OH 383.37 8-38 4-OMe CHF2 403.35 8-39 4-Amino-3-hydroxy Me 388.36 8-40 4-OMe CHO 381.35 8-41 4-OMe C═CH 377.37 8-42 4-OMe Et 381.4 8-43 4-OMe CH═CH2 379.38 8-44 3,4-Diamino Me 367.37 8-45 4-Amino-3-nitro Me 397.36 8-46 4-Methylamine-3-nitro Me 411.38 8-47 3-Dimethylamino Me 380.41 8-48 2,4-Dinitro-3- Me 470.41 dimethylamino 8-49 4-Nitro-3-dimethylamino Me 425.41 8-50 2-Nitro-3-dimethylamino Me 425.41 8-51 4-Dimethylamino-3-nitro Me 425.41 8-52 4-Ethylamino-3-nitro Me 425.41 8-53 4-Dimethylamino Me 380.41 8-54 3-Formyl-4-nitro Me 410.35 8-55 4-Amino-3-nitro Me 413.36 8-56 3-Fluoro-4-nitro Me 400.33

TABLE 8-2

Compound No. R³ = R² = MS(MH⁺) 8-57

Me 451.45 8-58

Me 465.47 8-59

Me 480.49 8-60

Me 495.48 8-61

Me 508.54 8-62

Me 452.44 8-63

Me 466.46 8-64

Me 467.45 8-65

Me 411.38 8-66

Me 415.35 8-67

Me 425.41 8-68

Me 429.37 8-69

Me 426.35 8-70

Me 454.45 8-71

Me 449.39 8-72

Me 454.45 8-73

Me 463.42 8-74

Me 447.46 8-75

Me 406.45 8-76

Me 421.46 8-77

Me 418.42

TABLE 9

Compound No. R³ = R² = MS(MH⁺) 9-1

Me 407.19 9-2

Me 404.39 9-3

Me 394.35 9-4

Me 397.4 9-5

Me 392.38 9-6

Me 326.32 9-7

Me 326.32 9-8

Me 394.4 9-9

Me 380.41 9-10

Me 395.43 9-11

Me 355.36 9-12

Me 393.37 9-13

Me 327.31 9-14

Me 406.2 9-15

Me 409.43 9-16

Me 372.3 9-17

Me 328.34 9-18

Me 397.44 9-19

Me 354.33 9-20

Me 354.33 9-21

Me 422.33 9-22

Me 342.36 9-24

Me 411.47

Experimental Example 1 In Vitro Antibacterial Activity

All compounds were dissolved in dimethyl sulfoxide (DMSO, Merck, purity >99.9%) to achieve final 1 mg/ml desired concentrations.

MICs (minimum inhibitory concentrations) were determined by the broth microdilution technique with 96-well microdilution plates. The antimicrobials were tested using the following MIC ranges: 0.008 to 8 μg/ml. The plates were filled with 100 μl of reinforced clostridial medium (Oxoid; Unipath Ltd., Basingstoke, United Kingdom) per well containing the final antibiotic concentrations. The plates were thawed and preincubated for 3 hours in an anaerobic chamber (Thermal, USA) containing an atmosphere of 80% N₂, 15% CO₂, and 5% H₂. The bacterial inocula were prepared by suspending growth from 48 hours cultures in reinforced clostridial medium. The final inoculum was approximately 1.0×10⁵⁻⁶ CFU/well. The plates were incubated for 48 hours at 37° C. in the anaerobic chamber. The MIC was defined as the lowest antibiotic concentration that inhibited visible growth. Ciprofloxacin, vancomycin and metronidazole were used as a positive control. The results are shown in Table 10.

TABLE 10 MIC of example compounds against C. difficile (μg/mL) Com- C. C. C. C. pound difficile difficile difficile difficile No. ATCC43255 ATCC700057 ATCC70092 IQCC23903 2-18 0.016-0.063 0.016-0.063 ≤0.008-0.063  0.032-0.063 2-46 0.032-0.125 0.032-0.25  0.063-0.25  0.125-0.25  5-14 0.125-0.25  0.125-0.5  0.125-0.25  0.125-0.5  2-49 0.063-0.25  0.063-0.25  0.063-0.5  0.063-0.25  3-11 ≤0.008-0.032  0.016-0.032 ≤0.008-0.032  ≤0.008-0.063  2-31 ≤0.008-0.032  0.016-0.032 0.016-0.032 0.016-0.063 1-2  0.032-0.125 0.032-0.125 0.032-0.125 0.063-0.25  3-21 0.016-0.032 0.016-0.063 0.016-0.063 0.032-0.063 2-38 0.016-0.032 0.016-0.032 0.032-0.063 0.016-0.032 3-30 0.032-0.063 0.063-0.125 0.063-0.125 0.063-0.25 

Experimental Example 2 In Vivo Antibacterial Efficacy

In vivo efficacy was evaluated in a hamster intestinal infection treatment model. Male Golden Syrian hamsters were purchased from Charles River Laboratories (Kingston, N.Y., USA) and were about 6 weeks of age, with weights ranging from 80 to 100 g at the start of the study. The animals were housed individually in filtered polycarbonate shoe-box style cages equipped with water bottles, and Harlan Teklab Global Diet 2016 was available ad libitum via food hoppers. The hamsters were pre-treated with clindamycin (1 mg/kg, p.o.) and vancomycin (50 mg/kg, p.o.), formulated in arabic gum, at Day 0. At Day 7, each hamster was inoculated via oral gavage with 0.5 mL of a suspension of C. difficile ATCC 43255 (10⁵ CFU/body, p.o.). To prepare this inoculum, C. difficile was grown in GAM agar (Japan) for 5 days at 37° C., and the bacteria were harvested by centrifugation, rinsed twice with arabic gum, resuspended in arabic gum and the exact bacteria density was determined using the dilution plate count method. Oral dosing of compounds, pulverized and formulated in arabic gum was commenced the following day (Day 8). Treatments were administered once a day for 5 consecutive days at specified doses (10, 2, and 0.4 mg/kg), with five hamsters per group. Controls were included an uninfected group and an infected but untreated group, and vancomycin was used as positive control. The hamsters were observed daily to record clinical signs (duration, time of onset, time of recovery or death), and animals in a lethargic, clearly moribund state were euthanized. A necropsy was performed on animals that were either found dead or were euthanized at the end of the study (37 days). The results are shown in FIG. 1 and FIG. 2.

Preparation Example 1

An injection preparation is prepared from the following components.

Components Amount Compound 1-2 200 mg Glucose 250 mg Distilled water for injection q.s. Total  5 ml

Compound 1-2 and glucose are dissolved in distilled water for injection, and the solution is added to a 5 ml ampoule, which is purged with nitrogen gas and then subjected to sterilization at 121° C. for 15 minutes to give an injection preparation.

Preparation Example 2

Film coated tablets are prepared from the following components.

Components Amount Compound 2-18 100 g Avicel (registered trademark)  40 g Corn starch  30 g Magnesium stearate  2 g TC-5 (registered trademark)  10 g Polyethylene glycol 6000  3 g Castor oil  40 g Ethanol  40 g

Compound 2-18, Avicel (registered trademark of microcrystalline cellulose, manufactured by Asahi Kasei Corporation, Japan), corn starch and magnesium stearate are mixed and kneaded, and the mixture is tabletted using a conventional pounder (R 10 mm) for sugar coating (manufactured by Kikusui Seisakusho Ltd., Japan). The tablets thus obtained are coated with a film coating agent consisting of TC-5 (registered trademark of hydroxypropyl methylcellulose, manufactured by Shin-Etsu Chemical Co., Ltd., Japan), polyethylene glycol 6000, castor oil and ethanol to give film coated tablets.

Preparation Example 3

An ointment is prepared from the following components.

Components Amount Compound 3-11  2 g Purified lanolin  5 g Bleached beeswax  5 g White petrolatum  88 g Total 100 g

Bleached beeswax is made liquid by heating, and thereto are added compound 3-11, purified lanolin and white petrolatum, and the mixture is heated until it becomes liquid. The mixture is stirred until it is solidified to give an ointment. 

1. A compound represented by the formula (I)

wherein X is or a fluorine atom; R is a hydrogen atom; R¹ is (1) cyclopropyl optionally substituted by 1 to 3 halogen atoms or (2) phenyl optionally substituted by 1 to 3 halogen atoms; R² is a hydrogen atom; alkyl optionally substituted by 1 or 2 substituents selected from the group consisting of a halogen atom and hydroxyl; alkoxy; haloalkoxy; a halogen atom; cyano; cyclopropyl; nitro; amino; formyl; alkenyl or alkynyl; R³ is (1) a fused heterocyclic group of the formula

wherein

represents a single bond or a double bond, X¹ is C(R⁵) or N, R⁴ is a hydrogen atom or alkyl, and R⁵ is (a) a hydrogen atom, (b) a halogen atom, (c) cyano, (d) nitro, (e) hydroxy, (f) alkyl optionally substituted by 1 to 3 halogen atoms, (g) alkenyl or alkynyl, (h) aryl, or (i) alkoxy optionally substituted by 1 to 3 halogen atoms, when X¹ is C(R⁵), R⁴ and R⁵ are optionally bonded to form a 5- or 6-membered ring optionally substituted by oxo, said fused heterocyclic group is optionally substituted by 1 or 2 substituents selected from the group consisting of a halogen atom, cyano, nitro, hydroxy and alkyl, (2) 3-pyridyl optionally substituted by 1 or 2 substituents selected from the group consisting of (a) a halogen atom, (b) cyano, (c) nitro, (d) hydroxy, (e) amino, (f) alkyl optionally substituted by 1 to 3 substituents selected from the group consisting of a halogen atom, alkylamino, dialkylamino and hydroxy, (g) alkenyl, alkynyl (h) aryl, (i) cycloalkyl, (j) alkoxy, (k) alkylamino, (l) dialkylamino, (m) phenylamino optionally substituted by 1 to 3 halogen atoms, (n) a cyclic amino group optionally substituted by alkoxycarbonyl, (o) formyl, (p) carbamoyl optionally substituted by alkyl optionally substituted by hydroxy, and (q) a 5- to 10-membered aromatic heterocyclic group optionally substituted by alkyl, (3) 4-pyridyl optionally substituted by a halogen atom, (4) a group of the formula

wherein one of Y¹, Y², Y³ and Y⁴ is N or N⁺(—O⁻), and the remaining three are each C(R²⁵), C(R²) and C(R²⁷), W is O, S, NH or N(R²³) R²³ is a hydrogen atom or alkyl, and R²⁴, R²⁵, R and R²⁷ are each independently, (a) a hydrogen atom, (b) cyano, or (c) nitro, (5) a group of the formula

wherein R²⁸ is a hydrogen atom or hydroxy, and R²⁹ is a hydrogen atom or alkyl, (6) a group of the formula

wherein R¹⁶ is (a) a hydrogen atom, (b) alkyl optionally substituted by 1 to 3 substituents selected from the group consisting of cyano, alkylamino and dialkylamino, (c) alkenyl optionally substituted by carboxy, (d) formyl, (e) carboxy, (f) carbamoyl, (g) —C(R¹⁷)═N—OH wherein R¹⁷ is a hydrogen atom, cyano or hydroxy, (h) a 5- to 10-membered aromatic heterocyclic group optionally substituted by alkyl, alkoxycarbonyl, carboxy or phenyl, or (i) cyano, or (7) a group of the formula

wherein R¹⁸ is a hydrogen atom or alkyl optionally substituted by 1 to 3 substituents selected from the group consisting of a halogen atom and phenyl, n is 0 or 1, R¹⁹, R²⁰ and R³³ are each independently, (a) a hydrogen atom, (b) a halogen atom, (c) cyano, (d) alkyl optionally substituted by 1 to 3 substituents selected from the group consisting of (i) a halogen atom (ii) cyano, (iii) hydroxy, (iv) amino, (v) alkylamino, (vi) dialkylamino, and (vii) a cyclic amino group optionally substituted by alkyl, (e) alkoxy, (f) amino optionally substituted by 1 or 2 substituents selected from the group consisting of (i) alkylcarbonyl optionally substituted by a cyclic amino group, (ii) alkylsulfonyl, (iii) carbamoyl, (iv) alkyl, cycloalkyl or cycloalkylalkyl, and (v) 5- to 10-membered saturated heterocyclic group, (g) carboxy, (h) alkoxycarbonyl, (i) carbamoyl optionally substituted by alkyl optionally substituted by amino, alkylamino, dialkylamino or alkoxycarbonylamino, (j) formyl, (k) a 5- to 10-membered aromatic heterocyclic group optionally substituted by alkyl, (l) —CH═N—OR²¹ wherein R²¹ is a hydrogen atom or alkyl optionally substituted by alkylamino or dialkylamino, (m) nitro, (n) a 5- to 10-membered saturated heterocyclic group optionally substituted by amino, (o) phenyl, or (p) —NHC(SMe)═CHCN
 2. (canceled)
 3. The compound of claim 1, wherein R³ is a fused heterocyclic group of the formula

wherein

, x¹ and R⁴ are as defined in claim 1, and said fused heterocyclic group is optionally substituted by 1 or 2 substituents selected from the group consisting of a halogen atom, cyano, nitro, hydroxy and alkyl, or a salt thereof. 4-6. (canceled)
 7. The compound of claim 1, wherein R³ is a group of the formula

wherein R²² is (a) a halogen atom, (b) cyano, (c) nitro, (d) alkyl optionally substituted by 1 to 3 substituents selected from the group consisting of a halogen atom, alkylamino, dialkylamino and hydroxy, (e) alkenyl, alkynyl, (f) aryl, (g) cycloalkyl, (h) alkoxy, (i) formyl, or (j) carbamoyl optionally substituted by alkyl optionally substituted by hydroxyl, or a salt thereof. 8-13. (canceled)
 14. The compound of claim 1, wherein R³ is a group of the formula

wherein R^(18a) is alkyl, and R^(19a) is (a) a halogen atom, (b) cyano, (c) alkyl optionally substituted by 1 to 3 substituents selected from the group consisting of (i) a halogen atom, (ii) cyano, (iii) hydroxy, (iv) amino, (v) alkylamino, (vi) dialkylamino, and (vii) a cyclic amino group optionally substituted by alkyl, (d) alkoxy, (e) amino optionally substituted by 1 or 2 substituents selected from the group consisting of (i) alkylcarbonyl optionally substituted by a cyclic amino group, (ii) alkylsulfonyl, (iii) carbamoyl, and (iv) alkyl or cycloalkyl, (f) carboxy, (g) alkoxycarbonyl, (h) carbamoyl optionally substituted by alkyl optionally substituted by amino, alkylamino, dialkylamino or alkoxycarbonylamino, (i) formyl, (j) a 5- to 10-membered aromatic heterocyclic group optionally substituted by alkyl, (k) —CH═N—OR²¹ wherein R²¹ is a hydrogen atom or alkyl optionally substituted by alkylamino or dialkylamino, or (l) nitro, or a salt thereof. 15-18. (canceled)
 19. The compound of claim 1, wherein R¹ is cyclopropyl, 2-fluorocyclopropyl or 2,4-difluorophenyl, or a salt thereof.
 20. The compound of claim 1, wherein R² is methyl, methoxy or a chlorine atom, or a salt thereof.
 21. A pharmaceutical composition comprising a compound of claim 1 or a salt thereof and a pharmaceutically acceptable carrier.
 22. An antimicrobial agent comprising a compound of claim 1 or a salt thereof. 23-26. (canceled)
 27. A method for preventing or treating a bacterial infection which comprises administering an effective amount of a compound of claim 1 or a salt thereof to a human or an animal. 